Positive T-cell Lymphoma Research Articles

Brentuximab Vedotin Followed By Allogeneic Stem-Cell Transplantation for Patients with CD30 Anaplastic or T Cell Non Hodgkin Lymphomas: A Study on Behalf of the SFGM-TC.

Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, has demonstrated efficacy alone or in combination with chemotherapy in CD30 refractory Non-Hodgkin Lymphoma (NHL). It has been approved in anaplastic large cell lymphoma (ALCL) and promising results have also been published in other CD30 positive T-cell lymphomas such as cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL). In patients with relapsing or refractory NHL, BV has mainly been proposed as a bridge for autologous or allogeneic transplantation (Allo-HSCT). Very few data are available about patients with T-cell NHL receiving Allo-HSCT after BV. The aim of our study was to study safety and efficacy of this procedure in a retrospective series of patients treated on behalf of SFGM-TC.Inclusion criteria were: - CD30 positive T cell NHL including ALCL, CTCL and PTCL, - Partial or Complete response after BV treatment, - Allogeneic HSCT performed after BV as last salvage treatment. BV was administered at 1,8mg/kg dose every 3 weeks in outpatient department. Allo-HSCT was performed according to institutional guidelines.Twenty-six patients receiving Allo-HSCT in France after salvage therapy including BV were identified. Patients characteristic are summarized in Table 1. With a median follow-up of 13 months (1.5-40), 8 patients relapsed and 7 patients died. Two-year OS and PFS were respectively 76% and 47%. Among patients with ALCL (n=15) 2 patients relapsed and 2 patients died. Whereas in the CTCL group (n=5), 5 patients relapsed and 1 patient died and in the PTCL group (n=6), 1 patient relapsed and 4 patients died. Two-year OS were 93%, 80% and 21% (p<0.001) and two-year PFS were 86%, 20% and 0% (p<0.001) for ALCL, CTCL and PTCL respectively. Two-years PFS for patients in CR before Allo-HSCT (n=16) was 67% whereas patients in PR (n=6) or who progressed before transplantation (n=3) have a 25% and 0% 2-years PFS respectively (p=0,08). In multivariate analysis, only anaplastic histology had a positive impact on OS or PFS. We compared data with a control group of patients with T-cell NHL (n=52) transplanted in the same centers during the same period, not receiving BV as a salvage treatment. Day-100 cumulative incidence of acute Grade 2-4 GVHD and Grade 3-4 GVHD were 39% [20-59] and 16% [1-30] in the BV group and 46% [27-66] and 19% [8-30] in the control group (p=NS). Two-years overall chronic GVHD and extensive chronic GVHD were 33% [9-56] and 22% [0-46] in the BV group and 39% [24-53] and 15% [0-26] in the control group (p=NS). Day-100 and 1-year NRM were 12% [0-25] and 16% [1-30] in the BV group and 4% [0-9] and 8% [1-15] in the control group (p=0,07). One-year relapse incidence was 37% [14-60] and 22% [10-34] in the BV and control groups respectively (p=0,27). BV was not associated with higher GVH, NRM or relapse incidence in multivariate analysis.In conclusion, BV followed by Allo-HSCT is an option for patients with advanced CD 30 positive T cell NHL. Immunotherapy targeting CD30 before Allo-HSCT is not associated with a higher rate of GVHD, NRM or relapse incidence. Patients with ALCL have a better survival than patients with PTCL or CTCL.Table 1Patients characteristicsAll patientsALCLCTCLPTCL(n=26)(n=15)(n=5)(n=6)Sexemale15 (58%)7 (47%)4 (80%)4 (67%)Age (at Allo-HSCT)median (range)47 (21-62)40 (21-59)50 (31-62)50 (46-59)Stade (at diagnosis)I-II4 (15%)3 (20%)-1 (17%)III-IV16 (62%)11 (73%)-5 (83%)unknown1 (4%)1 (7%)--NA5 (19%)-5 (100%)-Auto-HSCT (before BV)patients8 (31%)5 (33%)-3 (50%)Lines of chemotherapy (before BV)median (ranges)2 (1-7)2 (1-4)4 (3-7)2 (1-3)Status (before BV)refractory18 (69%)9 (60%)5 (100%)4 (66%)relapsing8 (31%)6 (40%)-2 (34%)cycles of BVmedian (ranges)4 (1-8)4 (1-8)4 (4-6)4 (1-4)Treatment associated with BVno20 (77%)11 (73%)5 (100%)4 (66%)GVD2 (8%)2 (13%)--CHP2 (8%)--2 (33%)DHAP1 (4%)1 (7%)--Radiotherapy1 (4%)1 (7%)--Time between diagnosis and Allo-HSCTMonths (range)21 (6-93)13 (6-93)23 (21-43)23 (12-76)Status before Allo-HSCTCR16 (62%)13 (87%)-3 (50%)PR6 (23%)2 (13%)4 (80%)-SD/PD3 (12%)-1 (20%)2 (33%)Donor typeMRD15 (57%)5 (33%)4 (80%)6 (100%)MUD7 (27%)6 (40%)1 (20%)-CBU2 (8%)2 (13%)--Haploidentical2 (8%)2 (13%)--Conditioning3 (50%)RIC17 (65%)9 (60%)5 (100%)MAC9 (35%)6 (40%)-3 (50%)Immunosuppressive agentsCyA5 (19%)4 (27%)-1 (17%)CyA/MMF10 (38%)4 (27%)5 (100%)1 (17%)CyA/MTX11 (42%)7 (47%)-4 (66%)Anti-thymocyte globulin11 (42%)8 (53%)1 (20%)2 (33%) DisclosuresOff Label Use: Brentuximab used for CD30+ cutaneous and peripheral T cell lymphoma.

In situ hybridisation for Epstein-Barr virus as a differential diagnostic tool for T- and natural killer/T-cell lymphomas in non-immunocompromised patients

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus infecting over 90% of humans and the infection persists for life. Although most people are asymptomatic, EBV infection may cause a continuous range of symptoms from transient to severe and protracted diseases depending on the immunological response of the individuals. EBV infects primarily B lymphocytes and rarely T and natural killer (NK) cells. It is implicated in around 1% of human tumours with the majority being haematological malignancies including Hodgkin lymphoma, B- and T-cell non-Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders (LPDs). As it is a ubiquitous virus the confirmation of EBV-related LPDs depends on the demonstration of the viral DNA by in situ hybridisation for EBV-encoded mRNA (EBER). In current practice, CD3 and EBER positive cytotoxic extranodal lymphomas in non-immunocompromised patients are generally considered as extranodal NK/T-cell lymphoma and accordingly EBER should be performed for such tumours except for the few clinically typical entities such as mycosis fungoides. This review focuses on the application of EBER in the diagnosis of various types of T- and NK/T-cell lymphomas in non-immunocompromised patients and the diagnostic pitfalls, especially their distinction from infectious mononucleosis-related LPD of T- and NK-cell origins and the diagnostic dilemma between various T-cell lymphoma entities with or without EBV association, including nodal cytotoxic EBV positive peripheral T-cell lymphoma.

Aggressive Subcutaneous Panniculitis-Like CD30+ Peripheral T-Cell Lymphoma with Diffuse EBER Expression.

T-cell lineage lymphoma with an intense membranous and paranuclear CD30 expression in the absence of ALK1 raises a differential diagnosis of peripheral T-cell lymphoma (PTCL), NOS and anaplastic large cell lymphoma (ALCL), ALK negative. However, Epstein-Barr virus is consistently negative in ALCL and is not considered an implicating factor in its pathogenesis. We describe a case of T-cell lymphoma showing anaplastic large cell morphology with scattered hallmark cells and a uniform CD30 and Epstein-Barr virus encoded early RNA (EBER) expression that primarily involved the subcutaneous tissue at presentation. On incisional biopsy, the neoplastic cells were positive for CD3, CD2, and CD30 while negative for LCA, CD20, PAX5, CD56, ALK1, and cytotoxic granules. Molecular analysis identified a positive T-cell receptor (beta and gamma) gene rearrangement by PCR. Proliferation index approached 100% and the patient had a rapidly progressive course; the subcutaneous lesions more than doubled in size within couple of weeks with new evidence for widespread systemic involvement. This case emphasizes a rare EBV association with a CD30 positive T-cell lymphoma where the morphologic and immunophenotypic findings are otherwise nondiscriminatory between PTCL, NOS and ALCL, ALK negative.

Epstein-Barr virus–positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection–associated T/NK-cell lymphoproliferative disorder: a case report

A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-γ chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection.

Follicular center helper T-cell (TFH) marker positive mycosis fungoides/Sezary syndrome

We identified 11 patients with CD10(+) cutaneous T-cell lymphoma by flow cytometry. All cases were CD4(+) and CD8(−). Three patients had extensive lymphadenopathy, systemic symptoms and an aggressive clinical course consistent with angioimmunoblastic T-cell lymphoma or peripheral T-cell lymphoma. However, 8 of the 11 patients had a prolonged disease course with gross morphology, histology and tumor cell phenotype indistinguishable from mycosis fungoides or Sezary syndrome. Immunohistochemical studies confirmed CD10 expression in seven of the eight cases and revealed the lymphoma cells were Bcl-6(+), PD-1(+), and EBV(−). Two had significant expression of CXCL-13(+). The findings indicate that lymphoma cells from mycosis fungoides or Sezary syndrome may express follicular center helper T-cell markers CD10, Bcl-6, and PD-1 and occasionally CXCL-13. The expression of these markers in some cases of mycosis fungoides/Sezary syndrome suggests follicular center helper T-cell differentiation and may lead to confusion in distinguishing mycosis fungoides/Sezary syndrome from other follicular center helper T-cell marker positive T-cell lymphomas with cutaneous manifestations.

P53 Prevents TCR-Dependent Peripheral T-Cell Lymphomagenesis From Chronically Stimulated T Cells.

AbstractAbstract 2401 Background.Compelling evidence suggests that chronic infections by various pathogens are linked to lymphoma development. The transformation process is supposed to be either direct (eg for EBV) or indirect. The association between Helicobacter pylori chronic infection and gastric marginal zone lymphoma (MZL) is the best characterized example for an indirect transformation. Several other pathogens such as hepatitis C virus, Campylobacter jejuni or Streptococcus Pneumoniae (Spn) are also suspected to promote B-cell lymphoma development through repeated stimulations of the BCR and/or inflammation. However, except for gastric MZL, animal models are lacking to study potential correlations between chronic infections and lymphoma development. Methods.To amplify and precipitate lymphomagenesis by precluding repair of DNA lesions potentially generated during chronic immune response, p53-deficient mice were used as a permissive model. Given the suspected role of carbohydrates from encapsulated bacteria such as Spn in promoting chronic lymphocytic leukemia, p53−/− (n=15) and p53+/− (n=53) mice were chronically injected with heat-killed Spn until disease development. P53-deficient mice chronically injected with PBS were used as control. Results.Unexpectedly, chronic injections of Spn promoted T-cell rather than B-cell lymphomagenesis in both p53−/− and p53+/− mice and shortened survival in p53+/− mice (P=.004). Whereas mostly thymic CD4+CD8+ double positive T-cell lymphomas have been described in p53-deficient mice, a vast majority of lymphomas observed following chronic Spn injections were of peripheral origin (TdT−) and exhibited an effector memory phenotype (CD44hiCD62LloCCR7−CD25−). Clonality and transferability of those peripheral T-cell lymphomas (PTCL) were established. Furthermore, lymphoma cells showed features of chronically stimulated T cells such as TCR, CD3 or CD4/CD8 co-receptor down-regulations along with PD-1 up-regulation. Several lines of evidence suggested a contribution of the TCR to the development of these PTCL: 1/all PTCL following Spn injections exhibited a Vß repertoire usage bias (Vß8 in 100%) consistent with a transformation process originating from a chronically-stimulated T cell by a pathogen-specific immunodominant peptide; 2/cyclosporin A, a strong TCR signaling inhibitor, decreased cell survival in vitro, and prolonged mice survival following transfer of lymphoma cells into recipient mice; 3/engraftment of CD8+ PTCL in MHC class I KO mice was significantly reduced compared to wild type mice (P<.0001). Finally in vitro survival of PTCL was strongly dependent on the addition of γc cytokines (IL-7 and IL-15) in agreement with the expression of CD122 and CD127 and their potential memory origin.The absence of B-cell lymphoma development in p53−/− mice and its very late onset in p53+/− mice (ie >450 days) compared to T-cell lymphoma prompted us to dissect the potential role of p53 in mature T-cell response in a context of chronic stimulation. WT and p53−/− negatively selected CD4+ and CD8+ T cells were repeatedly (ie every 7–10 days) stimulated in vitro using anti-CD3/anti-CD28-coated beads. In agreement with previous reports, no significant difference of cell viability was observed after the first or the second stimulation confirming the minor role of p53 in initial activation and proliferation as well as in activation-induced cell death. Nonetheless, a dramatic increase in cell viability was observed 48h after the third stimulation of p53−/− T cells, indicating a crucial function of p53 in deletion of chronically activated T cells. Conclusion.Chronic stimulations with heat-killed Spn unexpectedly increased peripheral T-cell lymphoma development in p53-deficient mice. Phenotypic characterization was consistent with a transformation process occurring in a pathogen-specific chronically-stimulated T cell. The incidence of p53 mutations is higher in T-cell than in B-cell mature malignancies in humans and the p53 pathway is functionally impaired in virtually all enteropathy-associated T-cell lymphomas, which are supposed to be a key model for an antigen-driven process. Therefore, aside from its known role in immature T-cell lymphoma development and in progression of B-cell malignancies, our work sheds light on a previously unsuspected physiopathological role of the p53 pathway in peripheral T-cell lymphomagenesis. Disclosures:No relevant conflicts of interest to declare.

A felületi röntgen irradiáció hatékonyságának értékelése mycosis fungoideses, primer cutan CD8+ agresszív epidermotrop citotoxikus T-sejtes lymphomás, primer cutan anaplasiás nagy sejtes lymphomás és primer cutan marginális zóna B-sejtes lymphomás betegeken

A felületi röntgen irradiáció hatékonyságának értékelése mycosis fungoideses, primer cutan CD8+ agresszív epidermotrop citotoxikus T-sejtes lymphomás, primer cutan anaplasiás nagy sejtes lymphomás és primer cutan marginális zóna B-sejtes lymphomás betegeken

Abstract 4575: Three-gene diagnostic classifier for ALK negative ALCL

Abstract Anaplastic Large Cell Lymphomas (ALCL) comprise approximately 12% of all T-cell Non-Hodgkin's lymphomas (T-NHL), representing a heterogeneous group whose definition, origin and relationship with other T-NHL remains controversial. The notion that ALCL strongly express CD30, and display recurrent chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene, led to recognition of two subsets, according to ALK expression. Although ALK positive ALCL can be readily diagnosed, ALK negative ALCL still lack unique genetic features and their distinction from other CD30 positive Peripheral T-Cell Lymphomas (PTCL) is not trivial. To unravel the regulatory network underlying lymphomagenesis of ALCL, and to discover new genomic classifiers for the recognition of ALK-positive and ALK-negative ALCL patients, we undertook a systematic approach of pathway discovery through a gene expression profiling meta-analysis of 309 cases, using data generated by five sets of experiments. In agreement with previous studies, unsupervised analyses were not able to distinguish ALCL from the other T-NHL categories. However, pathway discovery and prediction analyses defined a minimum set of genes useful for the stratification of ALK negative ALCL and strengthened the hypothesis that ALCL correspond to a distinctive pathological subgroup within T-NHL. Application of RT-qPCR in independent data sets of cryo-preserved and formalin-fixed paraffin embedded samples confirmed the gene expression profiling predictions and validated a simple model based on the measurement of three genes. These data suggest the possibility to translate RT-qPCR protocols to routine clinical settings as a new approach to precisely define T-NHL and to select more appropriate therapeutic protocols. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4575. doi:1538-7445.AM2012-4575

Epstein-Barr Virus–Positive T-Cell Lymphoma Involving the Lacrimal Gland of an Adult

Cost-effectiveness of Medications Compared With Laser Trabeculoplasty in Patients With Newly Diagnosed Open-Angle Glaucoma

Radiographically Negative, Asymptomatic, Sentinel Lymph Node Positive Cutaneous T-Cell Lymphoma in a 3-Year-Old Male: A Case Report

We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB) was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

Epstein-Barr virus–positive T-cell lymphoma cells having chromosome 22q11.2 deletion: an autopsy report of DiGeorge syndrome

Reported herein was the first autopsy case of Epstein-Barr virus-associated T-cell lymphoma in a 25-year-old man with DiGeorge syndrome. Systemic lymph nodes demonstrated diffuse encasement by large lymphoma cells positive for CD45, CD2, CD3, CD5, CD7, CD8, TIA1, and granzyme B, accompanied with marked hemophagocytosis. Almost 100% of lymphoma cells were both EBER- and LMP-1-positive, and EBNA2-negative. The rearrangement of T-cell receptor β gene was proved by polymerase chain reaction. Clinical and pathologic features coincided with Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorder preceded by chronic active Epstein-Barr virus infection. A fluorescence in situ hybridization using paraffin-embedded tissues demonstrated a mosaic chromosome 22q11.2 deletion with both host cardiac myocytes and lymphoma cells, suggesting that Epstein-Barr virus-associated T-cell lymphoma was associated with and derived from the cells carrying the chromosomal abnormality. Furthermore, the lymphomagenesis of our case correlated with defect of cellular immunity in DiGeorge syndrome.

Bortezomib Induces Caspase-9-Mediated Apoptosis through Activation of the BH3-Only Proteins Noxa, Bik and Puma In Both ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma Cells

AbstractAbstract 2847Anaplastic large cell lymphoma (ALCL) is a CD30 positive T-cell lymphoma that can be divided into a systemic and a primary cutaneous type. Systemic ALCL can be further divided into an anaplastic lymphoma kinase (ALK) expressing type and an ALK-negative type. Despite intensive treatment regimens, the disease will be fatal in 20–30% of the systemic ALK-positive and 50–70% of the systemic ALK-negative ALCL patients. A recent study in primary ALCL samples has demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in ALCL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In this study, we therefore investigated if bortezomib can induce apoptosis of cultured lymphoma cells of three systemic ALK-positive and three ALK-negative ALCL patients and seven ALCL cell lines and we examined the mechanisms by which bortezomib induced cytotoxicity in these ALCL cells.Treatment with bortezomib resulted in induction of apoptosis in all ALK-positive and ALK-negative ALCL patient samples and ALCL cell lines tested, when we compared the percentage cell death with the non-neoplastic CD4- and CD8-positive PBMC and tonsil T-cells from healthy donors. The lethal dose (LD50) varied between 54nM and more than 100nM after 24 hours and varied between 21nM and 52nM after 48 hours of exposure. ALK-negative ALCL cases were more sensitive to bortezomib and showed significant lower LD50 values than ALK-positive ALCL cells. We show that bortezomib-induced cell death in ALK-positive and ALK-negative ALCL is dependent on caspase-9 and/or caspase-8 mediated apoptosis and that bortezomib induces depolarization of the mitochondrial membrane. mRNA-expression and protein analysis revealed clearly upregulation of the BH3-only proteins Noxa, Bik and Puma, resulting in Bak and Bax release from the anti-apoptotic proteins Mcl-1 and Bcl-2. We also demonstrated that ALCL cells relatively resistant to bortezomib were characterized by high expression of Bcl-2A1, suggesting the possibility of pre-defining patients most likely to benefit from bortezomib therapy.Our preclinical data support the therapeutic application of bortezomib as potential drug in the treatment of ALCL, especially ALK-negative ALCL patients to improve their prognosis. Disclosures:No relevant conflicts of interest to declare.

Phase III Placebo-Controlled Trial of Denileukin Diftitox for Patients With Cutaneous T-Cell Lymphoma

PURPOSE This phase III, placebo-controlled, randomized trial was designed to investigate efficacy and safety of two doses of denileukin diftitox (DD; DAB(389)-interleukin-2 [IL-2]), a recombinant fusion protein targeting IL-2 receptor-expressing malignant T lymphocytes, in patients with stage IA to III, CD25 assay-positive cutaneous T-cell lymphoma (CTCL), including the mycosis fungoides and Sézary syndrome forms of the disease, who had received up to three prior therapies. The primary end point was overall response rate (ORR). PATIENTS AND METHODS Patients (N = 144) with biopsy-confirmed, CD25 assay-positive CTCL were randomly assigned to DD 9 microg/kg/d (n = 45), DD 18 microg/kg/d (n = 55), or placebo infusions (n = 44), administered for 5 consecutive days every 3 weeks for up to eight cycles. Patients were monitored for drug efficacy, clinical benefit, and safety of DD. RESULTS ORR was 44% for all participants treated with DD (n = 100; 10% complete response [CR] and 34% partial response [PR]) compared with 15.9% for placebo-treated patients (2% CR and 13.6% PR). ORR was higher in the 18 microg/kg/d group versus the 9 microg/kg/d group (49.1% v 37.8%, respectively), and both doses were significantly superior to placebo. Progression-free survival (PFS) was significantly longer (median, > 2 years) for both DD doses compared with placebo (median, 124 days; P < .001). Rates of moderately severe and severe adverse events (AEs) were slightly higher in the DD groups, whereas moderate and mild AEs were similar to placebo. No statistical differences were observed for drug-related serious AEs. CONCLUSION DD had a significant and durable effect on ORR and PFS with an acceptable safety profile in patients with early- and late-stage CTCL.

L-Asparaginase-Induced Complete Response in a Relapsed Patient with Epstein-Barr Virus and Cytotoxic Peripheral T-Cell Lymphoma Not Otherwise Specified

We present a patient with Epstein-Barr virus (EBV)-positive cytotoxic peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) who was successfully treated using only L-asparaginase. A 46-year-old Japanese man was diagnosed with EBV-positive cytotoxic PTCL-NOS. Although he underwent chemotherapy using multiple agents, he relapsed with hemophagocytic syndrome. L-asparaginase treatment was initiated at 6,000 U/m(2) on days 1, 3, 5, 10, and 12 together with prednisolone at 1 mg/kg. Although he developed grade 2 liver dysfunction and grade 2 coagulopathy, the patient achieved complete response status. Finally, he underwent allogeneic bone marrow stem cell transplantation, and he is currently still alive without disease at 24 months after the start of L-asparaginase therapy.

Expression of Cancer-Testis Antigens in Non-Hodgkin's Lymphomas

Cancer-testis (CT) antigens are expressed in a variety of malignant tumors but in normal adult tissues solely in testicular germ cells. Based on this tumor-associated expression pattern, CT antigens are considered valuable targets for immunotherapy. While CT antigens have been studied in many solid tumors, much less is known about their presence in neoplasms of the hematopoetic system such as Non Hodgkin's Lymphoma (NHL).Aims: To analyze the expression of 10 CT antigens in NHL by immunohistochemistry (IHC) using tissue microarray (TMA) technology, and to correlate its expression with histologic subtypes.Patients and Methods: Formalin-fixed paraffin-embedded tissues of 116 NHL cases dating from June 2003 to June 2007 were retrieved from the archives of the Department of Pathology, Federal University of São Paulo, Brazil. Two TMA blocks were generated comprising three cores/NHL case, as well as positive (testis) and negative (reactive lymph nodes) control tissue cores. The following monoclonal antibodies (mAbs) (to the following antigens) were used for IHC analysis: MA454 (MAGE-A1), M3H67 (MAGE-A3), 57B (MAGE-A4), CT7-33 (CT7/MAGE-C1), CT10#5 (CT10/MAGE-C2), E978 (NY-ESO-1), 219-510-23 (LAGE-1 and NY-ESO-1), #26 (GAGE) and SSX-2#7 (SSX-2). Two observers scored all slides independently and cases with loss of all three punches and/or missing tumor tissue were excluded from analysis.Results: The number of cases which could not be evaluated due to loss of tissue core and/or missing tumor differed, ranging between 8 for mAb #26 to 12 for mAbs MA454, CT10#5 and 219-510-23. 7/116 NHL cases were missing in all slides. 14/109 (12.8%) NHL cases expressed at least one CT antigen: diffuse large B-cell lymphoma (DLBCL) 9/58 (15.5%); anaplastic large cell lymphoma (ALCL) 1/3; follicular lymphoma (FL) 1/10 (10%); lymphoplasmacytic lymphoma (LPL) 1/3; peripheral T-cell lymphoma (PTCL) 1/9 and histiocytic lymphoma (HL) 1/1. No CT antigen expression was present in lymphoblastic lymphoma (5), mantle cell lymphoma (2), small lymphocytic lymphoma (6), marginal zone lymphoma (4), MALT lymphoma (5) and mycosis fungoides (3). The most frequently expressed CT antigens were: GAGE 6/108 (5.5%), NY-ESO-1 5/105 (4.7%), CT7 5/106 (4.7%), MAGE-A1 4/104 (3.8%) and MAGE-A3 4/107 (3.7%). According to cell origin, positivity of CT antigens was more prevalent in B-cell NHL (11/91; 12.1%) than in T-cell NHL (1/15; 6.7%). NY-ESO1 5/91(5.5%) was the most frequently expressed CT in B-cell NHL, followed by GAGE 4/91 (4.4%), MAGE-A1 3/91 (3.3%), MAGE-A3 3/91 (3.3%), CT7 3/91 (3.3%) and LAGE 3/91 (3.3%). The only positive T-cell lymphoma case expressed MAGE-A1 and GAGE.Conclusions: Expression of CT antigens in NHL is limited. In the present TMA-based IHC analysis, only 12% of NHLs express at least one CT antigen, with DLBCL showing the highest incidence and NY-ESO-1 being the most prevalent antigen. In spite of the low incidence, presence of CT antigens could offer the opportunity of vaccine-based immunotherapy in selected cases of NHL.

CD20 positive mycosis fungoides: a case report

CD20 positive T-cell lymphoma is extremely rare. Most reported cases are nodal peripheral T-cell lymphomas (PTCLs) or rarely lymphoma involving extranodal sites. Only two cases of CD20 positive T-cell lymphomas involving the skin have been previously reported and were classified as PTCL - not otherwise specified. We present a case report of a 53-year-old man with CD20 positive mycosis fungoides (MF) involving the skin and an inguinal lymph node. The patient presented with erythematous patches and plaques of the right lower extremity and was found to have an enlarged inguinal lymph node 2 years later. Flow cytometric immunophenotyping of the lymph node aspirate showed a CD2+/CD3+/CD4+/CD5+/CD7-/CD8- T-cell population with CD20 co-expression. Molecular studies by polymerase chain reaction demonstrated clonal T-cell receptor gamma chain gene rearrangement. Immunoglobulin heavy and light chain gene rearrangements were not identified. To our knowledge, this is the first case of CD20 positive MF involving a lymph node to be reported in the literature.

Primary central nervous system lymphomas: Indian experience, and review of literature

Primary central nervous system lymphomas (PCNSLs) are a rare form of non-Hodgkin's lymphoma which arise within and remain confined primarily to the central nervous system (CNS). They generally account for 1-2% of all primary brain tumors and are reported to be on the rise due to the Acquired Immune Deficiency Syndrome (AIDS) epidemic. To study the clinicopathological and immunophenotypic characteristics of PCNSLs and look for any differences in PCNSLs reported in India from those in other countries. All cases of PCNSLs between January 1998 and December 2006 were reviewed. Presence of lymphadenopathy, organomegaly and bone marrow study was done to exclude the possibility of secondary involvement by lymphoma. The diagnosis was confirmed by histopathology with Hematoxylin and Eosin and reticulin stains. Immunohistochemistry (IHC) with leucocyte common antigen (LCA), CD 20 and CD 3 was performed on available blocks. The immune status was evaluated by clinical examination and human immunodeficiency virus (HIV) serology (since 1996). In a 19-year study period, there were 56 patients of PCNSLs, accounting for 1.07% of all intracranial neoplasms. The patients ranged from 10-75 years of age with a median age of 42 years. Barring one patient who was HIV positive, all the others were immunocompetent. All cases were diffuse large cell lymphomas on histopathology. IHC with LCA and CD 20 revealed positivity in 100% and 86.4% cases respectively. There was a single case of CD 3 positive T-cell lymphoma. In the present study, PCNSLs occurred in young immunocompetent patients and majority were diffuse large B cell lymphomas.

LARGE GRANULAR LYMPHOCYTIC LEUKEMIA VERSUS GAMMA DELTA T-CELL LYMPHOMA: A CLINICAL CHALLENGE.

Background We are describing an interesting case that challenged our interpretation between large granular lymphocytic leukemia (LGL) and gamma delta T-cell lymphoma. LGL is a rare leukemia with a median age onset at 55 years having characteristic morphology, multiple autoimmune disorders, and an indolent clinical course in females, whereas gamma delta positive T-cell lymphoma is an uncommon aggressive non-Hodgkin9s lymphoma variant found in young males. Case Presentation A 53-year-old female with a 3-year history of pancytopenia, recurrent upper respiratory infections, and lupus presented with worsening cytopenia. CT scan of the chest, abdomen, and pelvis showed diffuse hepatosplenomegaly with minimal lymphadenopathy. Peripheral blood smear showed pancytopenia with a minor population of large granular lymphocytes (WBC 1.1 L, RBC 3.2 L, Hb 11 L, platelets 86 L, neurophil 0.1 L, lymph 80 H). Bone marrow biopsy revealed 40 to 50% cellularity with involvement by T-cell lymphoproliferative disorder of TCR-gamma/delta immunophenotype; positive for CD2, CD3, CD5 dim, and CD7dim and negative for CD4, CD8, CD16, CD25, and CD56, with variable CD57 expression. Molecular studies for T-cell receptor gene rearrangement showed no evidence of T-cell clonal population. The cytogenetics were normal diploid. Since the patient had features of both LGL and T-cell gamma delta lymphoma, the case was referred to M.D. Anderson Cancer Center for a second opinion, where LGL was the final diagnosis. Patient was treated with cyclosporine and she responded well to it, resolving her pancytopenia. Discussion In view of the characteristics of these rare disorders our patient was CD8 negative and CD3 positve. CD8 negativity is not consistent with LGL, yet she had systemic signs and symptoms, including fatigue, sweats, recurrent infections, and arthritis, which are main clinical features of T-cell LGL. In addition, CT scan findings of mild hepatosplenomegaly, which is observed in 20%, and IgM and IgG monoclonal gammopathy, which is present in 8% of patients, supported the diagnosis of LGL. A female patient with an indolent clinical course and 72% lymphocytes in the peripheral blood also argues against the features of T-cell gamma delta lymphoma. This case highlights the clinical spectrum of LGL proliferations and T-cell gamma delta lymphoma and how immunophenotypic and genotypic studies can help establish the diagnosis and modify the treatment.

Primary cutaneous aggressive epidermotropic CD8 positive cytotoxic T-cell lymphoma of the ear

We report a case of an epidermotropic CD8+ cutaneous T-cell lymphoma which initially presented as an ulcerated lesion of the pinna. Although T-cell lymphomas may present as cutaneous lesions, the ear is rarely involved. This uncommon presentation and the need for multiple biopsies means that the diagnosis of these lesions may be delayed or missed. A high index of suspicion is required when evaluating cutaneous lesions in the head and neck area.

CD-3 positive extranodal T-cell lymphoma of nasal type with skin involvement

A 40-year-old previously healthy lady presented with nasal obstruction and localized plaques over the right arm. She developed complete nasal obstruction due to a mass in the right nasal cavity and skin lesions that ulcerated to present as ecthyma gangrenosum like lesions. Patient's condition deteriorated fast and she developed icterus with fatal outcome within 4 weeks of developing skin lesions. Nasal and skin biopsy revealed angiocentric T-cell lymphoma, which on immuno-phenotyping revealed CD-3 positive; and CD-20, CD-30, ALK and EMA negativity. She was seronegative for HIV. Final diagnosis of CD-3 positive extranodal T-cell lymphoma of nasal type was made. Extranodal T-cell lymphomas are very aggressive NHLs with poor prognosis. Prognosis depends on histology, stage of the disease and sites of involvement. NK/T cell lymphoma of nasal type is common with EBV association. Skin involvement is rare and is also an indicator of poor prognosis.