Cytokine/Chemokine Expression with Protein Arrays Identifies Three Subsets of T-Cell Lymphomas with Differented Immunological Profiles,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3473-3473
Author(s):  
Santiago Mercadal ◽  
Antonio Martinez ◽  
Lluis Colomo ◽  
Elias Campo ◽  
Armando Lopez-Guillermo
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Stage Iv ◽  
Large Cell ◽  
Protein Microarrays ◽  
High Expression ◽  
Antibody Array ◽  
Image Analysis System ◽  
T Cell Lymphomas

Abstract Abstract 3473 Background: Only a few studies have addressed the expression of cytokine/chemokine in T-cell lymphomas. The aim of this study was to analyze the cytokine/chemokine protein expression profiles and to correlate them with the pathological manifestation of T-cell lymphomas. Patients and methods: Samples at diagnosis from 19 patients were T-cell lymphoma (unspecified peripheral T-cell lymphomas (PTCL), 10 cases; angioimmunoblastic (AITL), 4; ALK-negative anaplastic large-cell (ALCL), 3 and ALK-positive ALCL, 2) and were studied by protein microarrays. The characteristics of the patients were as follows: 11/8 M/F; median age, 55 years. 50% of patients were stage IV, 69% had extranodal involvement, 79% high LDH and 66% high β2 microglobulin. The high or high-intermediate risk IPI and PIT score were 62% and 61%, respectively. We have analyzed the expression of 174 cytokines by using a highly sensitive and specific antibody array containing single band specific primary antibodies duplicate. Chemolumiscence detection was performed by a HRP-conjugated streptavidin in an image analysis system. Densitometry analysis of unsaturated pixels was performed with Image Gauge software and an endogenous housekeeping gene was used to normalize results. Unsupervised clustering analysis was then performed. Results: Three clusters were obtained. Cluster 1 included 5 ALCL, 2 PTCL and 1 AITL, with a cytokine/chemokine profile that had high expression of IL21R, MIG, PDGF AA/AB, LIGHT, IL10, MIP1γ, MIP3α and IL13. Cluster 2 was composed by 5 PTCL and 1 AITL and exhibited a profile characterized by the high expression of L-SELECTIN, MMP1, IL1RII, SIGLEC 5, IL10R, IL1β, IL18BPA, FGF7, IL13RAα2, GMCSF, SDF1β, LIF, IL1Rα and IL11. Finally, the analysis defined a cluster 3 constituted by 2 AITL and 3 PTCL with a cytokine/chemokine profile that showed the high expression of TIMP1, NT4, ITAC and IGBP6. Detailed initial features and outcome of the patients according to the clusters are detailed in the table. Cluster 1 had better survival than the other groups (p=0.01). Summary: T-cell lymphomas show three different cytokine/chemokine patterns as was determined by protein microarrays. Cluster 1 was well characterized with the presence of all ALCL and better survival. Disclosures: No relevant conflicts of interest to declare.

T-cell lymphomas: immunologic, histologic, clinical, and therapeutic analysis of 63 cases.

1988 ◽  
Vol 6 (10) ◽  
pp. 1584-1589 ◽  
Author(s):  
B Coiffier ◽  
F Berger ◽  
P A Bryon ◽  
J P Magaud
Keyword(s):  
T Cell ◽  
Clinical Presentation ◽  
Performance Status ◽  
Stage Iv ◽  
Poor Performance ◽  
Large Cell ◽  
Response To Therapy ◽  
Poor Performance Status ◽  
T Cell Lymphomas ◽  
Stage Iv Disease

Sixty-three patients with T-cell lymphoma (TCL) were analyzed to correlate morphological and immunological features with clinical presentation, response to therapy, and survival. Clinical presentation was severe, with 59% of patients having stage IV disease, 60% B symptoms, 35% poor performance status, 44% large tumoral mass, and 40% a high number of extranodal localizations. Morphological subtypes were small-cell in four cases, diffuse-mixed in 29 cases, monomorphic medium-sized in two cases, immunoblastic in 21 cases, anaplastic large-cell in four cases, and unclassified in three cases. Immunological phenotypes were immature T in 11 cases, CD4 in 26 cases, CD8 in 13 cases, and undefined (CD4 + CD8) in ten cases. Response to therapy was poor except for the 39 patients treated by an intensive and sequential regimen (non-Hodgkin's lymphoma [LNH]-80 or LNH-84) that gave a 77% complete remission (CR) rate with a 23% relapse rate. Median survival was 35 months. No correlation was found between morphological subtypes and other variables. Helper (CD4) phenotype seemed to have a better prognosis than other phenotypes. Variables associated with long survival for all the patients were localized disease and absence of large tumoral mass and for the subgroup of patients treated by the LNH regimens CD4 phenotype, absence of B symptoms, absence of a large tumoral mass, and less than two extranodal sites of disease.

BLIMP1 Is Commonly Inactivated In Anaplastic Large T-Cell Lymphomas (ALCL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2634-2634
Author(s):  
Michela Boi ◽  
Andrea Rinaldi ◽  
Roberto Piva ◽  
Paola MV Rancoita ◽  
Paola Bonetti ◽  
...  
Keyword(s):  
T Cell ◽  
Somatic Mutation ◽  
Conflicts Of Interest ◽  
Stop Codon ◽  
Expression Profiles ◽  
Rank Test ◽  
Distinct Subgroup ◽  
T Cell Lymphomas ◽  
Genomic Aberrations ◽  
Genetic Events

Abstract Abstract 2634 ALCL has been separated in two distinct subtypes based on the presence or absence of translocations involving the ALK gene. It is accepted that ALK+ALCL is a distinct subgroup which shares a unique phenotype, with well defined genetic and clinical features. Although the clinical presentations, translocations and genetic events vary between ALK+ and ALK-ALCL, the relationship between these two ALCL subtypes and whether ALK-ALCL may represent a subset of peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS), remains unclear. In this regard, the WHO Classification classifies ALK-ALCL as a provisional entity. A better understanding of the underlying genetics would provide critical explanations to answer some of these questions. With the aim of identifying the genetic events underlying the pathogenesis of ALCL, we studied a series of 69 cases of ALCL (34 ALK-, 35 ALK+) with high-density genome wide SNP-based arrays. Methods. DNA was extracted from frozen biopsies. DNA profiles were obtained using the Affymetrix GeneChip Human Mapping SNP6 arrays. Differences in frequencies between subgroups were evaluated using Fisher's exact test. A subset of cases also had available gene expression profiles. Clinical data were available in half of the cases and genomic lesions were evaluated for their impact on clinical outcome with the log-rank test. Results. The most common losses were at 6q21, 17p13 (19%), 13q22.3 (15%), 3p21.31, 13q32.3 (14%), 1p13.3, 16q23.1 (WWOX) (13%), 16q23.3–24.1 (12%), 1p33 and 16q22.1 (10%). The most common gains occurred at 8q22 (20%), 1q (13%), 7q (10–15%; CDK6, 15%), 8q24 and 9p24.1 (10%). ALK-ALCL displayed a higher number of genomic aberrations in comparison with ALK+ALCL. The lesions presenting major differences included: -6q21 (35% vs 6%; P=0.002), -1p13 (26% vs 3%, P=0.001), -3q22 (26% vs 0%, P=0.001), -4q12-q26 (18% vs 0%; P=0.009), +9p21 (17% vs 0%, P=0.009), -17p13 (TP53, 26% vs 6%, P=0.019). The deletions at 6q21 targeted the gene PRDM1, coding for BLIMP1. The whole coding sequence of PRDM1 has been sequenced in 33 ALK- ALCL samples. Only one somatic mutation, inducing a stop codon, was identified, in one case bearing copy neutral loss of heterozygosity (cnLOH) spanning PRDM1 locus, suggesting a loss of functional protein in this patient. As a whole, 38% of ALK-ALCL presented loss of at least one allele of PRDM1. Only two cases were observed with complete gene loss: the ALK-case with somatic mutation plus cnLOH, and one ALK+ case with homozygous deletion. The presence of 6q21 deletion had an impact on progression free survival among all ALCL (P=0.048), likely reflecting its association with ALK-ALCL, but not when considering ALK- patients only. Xenografts derived from primary ALCL samples bearing 6q21 loss presented decreased BLIMP1 expression level. The detection of PRDM1 loss was present also in cell lines, in which also a decreased level of BLIMP1 RNA and protein was observed. Additional genes, members of PRDM1 pathway, were identified as targets of focal deletions. Conclusions. A series of recurrent lesions has been identified in ALCL. Alongside TP53 loss, inactivation of PRDM1 by genomic losses or somatic mutations was the most common detected lesion, and was more frequently inactivated in ALK-ALCL. PRDM1, encoding BLIMP1, a master regulator of T-cells differentiation, appears as a central gene in ALCL pathogenesis. Other genes, belonging to the same pathway, were found to have focal genomic aberrations in a smaller number of cases. Disclosures: No relevant conflicts of interest to declare.

The Clinical Significance Of Activated p-AKT Expression In Peripheral T-Cell Lymphomas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4315-4315
Author(s):  
Jung Yong Hong ◽  
Min Eui Hong ◽  
Seok Jin Kim ◽  
Jun Ho Jang ◽  
Kihyun Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Significance ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Akt Pathway ◽  
Serine Threonine Kinase ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

Abstract Background The oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway mediates diverse prosurvival signals and promotes the malignant phenotype of cancer cells through multiple downstream pathways. We aimed to define the prognostic role and clinical significance of p-AKT expression in peripheral T-cell lymphomas (PTCLs). Methods We evaluated the p-Akt expression in patients with PTCLs using tissue microarray(TMA) technology. The intensity of p-AKT staining was scored as 0, 1, 2, and 3 and the proportion of p-AKT positive cells was scored from 0% to 100%. p-AKT expression score was expressed as arbitrary units (AUs), calculated by multiplying the intensity score by the proportion score. Results A total of 63 PTCL patients were analyzed (PTCL not otherwise specified [PTCL-NOS, n=16], angioimmunoblastic T-cell lymphoma [AITL, n=19], and anaplastic large cell lymphoma [ALCL, n=11] and natural killer T-cell lymphoma [NKTCL, n=17]). The upper limit of the third quartile (Q3) of the AU values was 120. High p-AKT group (AU>Q3) included a higher proportion of NKTCL (41.7%) and ALCL (33.3%) subtypes, while low p-AKT group (AU≤Q3) included higher proportion of AITL (37.3%) and PTCL-NOS (25.0%) subtypes. High p-AKT group showed substantially poorer overall survival (OS) (median OS, 2.3 months vs. 25.2 months, P< 0.001) compared with the low p-AKT group. Multivariate analysis showed that high p-AKT group retained its significance as an independent prognostic factor for poor OS (hazard ratio [HR] 6.5; 95% confidence interval [CI], 2.7 – 15.9; P< 0.001) and poor PFS (HR 4.7, 95% CI; 2.1 – 10.6, P< 0.001).< 0.001) compared with the low p-AKT group. Conclusion PTCLs having high p-AKT expression showed a significantly worse survival than patients with low p-AKT expression. Thus, more effective treatment approaches are needed for this subset of patients with PTCLs, and we suggest inhibition of PI3K/AKT pathway may be a promising therapeutic strategy in PTCLs. Disclosures: No relevant conflicts of interest to declare.

Striking Association of Lymphoid Enhancing Factor (LEF1) Overexpression and DUSP22 rearrangements in Anaplastic Large Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Aishwarya Ravindran ◽  
Andrew L. Feldman ◽  
Rhett P. Ketterling ◽  
Surendra Dasari ◽  
Karen Rech ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Predictive Value ◽  
Triple Negative ◽  
Conflicts Of Interest ◽  
Large Cell ◽  
Nuclear Staining ◽  
Molecular Features ◽  
T Cell Lymphomas ◽  
Alk Positive

Introduction: Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell lymphomas classified into ALK-positive and ALK-negative. The ALK-negative ALCLs are a genetically heterogeneous group that includes DUSP22-rearranged, TP63-rearranged and triple-negative cases. The DUSP22-rearranged ALCLs characteristically grow in a diffuse sheet-like pattern and are composed of intermediate-sized monomorphous hallmark cells, admixed with smaller cells with prominent nuclear indentations and occasional central nuclear pseudo inclusions (King RL et al, Am J Surg Pathol. 2016). Further, DUSP22-rearranged ALCL is a molecularly distinct subset of ALCL with a unique immunogenic phenotype that portends a favorable prognosis (Luchtel RA et al. Blood 2018). Lymphoid enhancer binding factor (LEF1) is a crucial nuclear mediator of the Wnt/ β-catenin pathway and a transcription factor involved in T-cell maturation. However, limited data exists on the association of LEF1 in T-cell lymphomas, including ALCL. The aims of this study were to explore LEF1 expression by immunohistochemistry in different subsets of ALCLs and to analyze the association of Wnt/ β-catenin pathway in this cohort. Methods: After approval by the institutional review board, we screened pathology reports from January 1, 1995 to December 31, 2019 and identified patients with a diagnosis of ALCL using our institutional database. Details on fluorescence in situ hybridization studies in ALK-negative cases were documented. Immunostaining for LEF1 and β catenin was performed on all cases where formalin fixed paraffin embedded tissue was available. The presence or absence of β catenin nuclear staining was recorded. LEF1 nuclear staining in the neoplastic ALCL cells was graded as negative (0), weak (1+), intermediate (2+) or strong (3+) and the percentage of LEF1-positive neoplastic cells was detailed (Figure 1). LEF1 scoring was performed by manual counting of the stained nuclei out of all tumor nuclei by two pathologists (A.R. and M.S.) and the grading was reviewed by another pathologist (P.J.K.). Results: We evaluated 45 ALCL cases, including 41 (91.1%) ALK-negative and 4 (8.9%) ALK-positive ALCLs. Among the ALK-negative ALCLs, there were16 DUSP22-rearranged, and 25 non-DUSP22-rearanged (7 TP63-rearranged and 18 triple-negative) cases. Fifteen (94%) of 16 DUSP22-rearranged ALCLs showed strong expression of LEF1 in &gt;75% tumor cells (Figure 2). In contrast, this strong and uniform LEF1 overexpression was only detected in 1 of 29 (3%) of the remaining ALCL cases (P &lt;.0001) (Table 1). We previously characterized a distinctive molecular signature in ALK-negative ALCLs with DUSP22-rearrangements using gene expression microarray analysis on frozen ALCL tissue samples (Luchtel RA et al. Blood 2018). On examining LEF1 gene expression in this previously published dataset, DUSP22 -rearranged cases had significantly higher LEF1 expression than any other genetic subtype (triple-negative, TP63-rearranged, or ALK-positive). Overall, mean LEF1 expression was 6.3-fold higher in ALCLs with DUSP22 rearrangements than in ALCLs without DUSP22-rearrangements (P=0.0001). LEF1 is a coactivator of the Wnt/β-catenin pathway; therefore, it is reasonable to hypothesize the overexpression of LEF1 may promote Wnt/β-catenin signaling. However, all LEF1-positive cases were negative for β-catenin by immunohistochemistry, suggesting that LEF1 overexpression is independent of the Wnt/β-catenin pathway signaling in these cases. Conclusions: There is a striking association between high LEF1 expression and DUSP22-rearrangements in ALCLs. The strong and uniform LEF1 expression pattern has a high positive predictive value (94%) and high negative predictive value (96%) for DUSP22- rearrangement in ALK-negative ALCLs (Table 2). The combination of characteristic morphologic and molecular features of DUSP22-rearranged cases with the unique LEF1 expression further emphasizes that DUSP22-rearranged ALCL represents a distinct clinicopathologic subset of ALCL. Disclosures No relevant conflicts of interest to declare.

Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2213-2219 ◽  
Author(s):  
Marcel W. Bekkenk ◽  
Maarten H. Vermeer ◽  
Patty M. Jansen ◽  
Ariënne M. W. van Marion ◽  
Marijke R. Canninga-van Dijk ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Size ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Skin Lesions ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
T Cell Lymphomas ◽  
Nor Phenotype ◽  
Peripheral T Cell Lymphomas

Abstract In the present study the clinicopathologic and immunophenotypic features of 82 patients with a CD30– peripheral T-cell lymphoma, unspecified, presenting in the skin were evaluated. The purpose of this study was to find out whether subdivision of these lymphomas on the basis of cell size, phenotype, or presentation with only skin lesions is clinically relevant. The study group included 46 primary cutaneous CD30– large cell lymphomas and 17 small/medium-sized T-cell lymphomas as well as 17 peripheral T-cell lymphomas with both skin and extracutaneous disease at the time of diagnosis. Patients with primary cutaneous small- or medium-sized T-cell lymphomas had a significantly better prognosis (5-year-overall survival, 45%) than patients with primary cutaneous CD30– large T-cell lymphomas (12%) and patients presenting with concurrent extracutaneous disease (12%). The favorable prognosis in this group with primary cutaneous small- or medium-sized T-cell lymphomas was particularly found in patients presenting with localized skin lesions expressing a CD3+CD4+CD8– phenotype. In the primary cutaneous T-cell lymphoma (CTCL) group and in the concurrent group, neither extent of skin lesions nor phenotype had any effect on survival. Our results indicate that peripheral T-cell lymphomas, unspecified, presenting in the skin have an unfavorable prognosis, irrespective of the presence or absence of extracutaneous disease at the time of diagnosis, cell size, and expression of a CD4+ or CD8+ phenotype. The only exception was a group of primary cutaneous small- or medium-sized pleomorphic CTCLs with a CD3+CD4+CD8– phenotype and presenting with localized skin lesions.

Primary Cutaneous T-Cell Lymphoma: Review and Current Concepts

2000 ◽  
Vol 18 (15) ◽  
pp. 2908-2925 ◽  
Author(s):  
Richard S. Siegel ◽  
Tomi Pandolfino ◽  
Joan Guitart ◽  
Steven Rosen ◽  
Timothy M. Kuzel
Keyword(s):  
Differential Diagnosis ◽  
T Cell ◽  
Gene Rearrangement ◽  
Medical Literature ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Cutaneous T Cell Lymphoma ◽  
T Cell Lymphomas ◽  
Skin Abnormalities ◽  
Indolent Disease

PURPOSE: Primary cutaneous T-cell lymphomas (CTCLs) encompass a wide variety of lymphomas that are characterized by the localization of the malignant lymphocytes to the skin at presentation. Advances in molecular biologic techniques, including immunophenotyping and gene rearrangement studies to determine clonality, have led to more frequent diagnosis of CTCL as well as more consistent subclassification of these entities. However, there continues to be confusion in the classification, prognosis, and management of patients with CTCL. The purpose of this review is to present a summary of the diagnosis, prognosis, and treatment of CTCL, with specific emphasis on mycosis fungoides (MF) and Sézary syndrome (SS). We also present a detailed discussion of the entities that make up the differential diagnosis of CTCL. DESIGN: We reviewed the medical literature on CTCL and other diseases that make up the differential diagnosis of CTCL. Results and CONCLUSION: MF and SS are the most common forms of CTCL. The etiology of this disease is still unknown. Patients may go for months to years with skin abnormalities before being diagnosed. MF/SS is an indolent disease and patients with T1 disease have a normal life expectancy. Patients who undergo transformation to large-cell lymphoma (8% to 23% of patients) have a poor prognosis, with mean survival ranging from 2 to 19 months. Treatment for MF/SS continues to be palliative. There are many new therapies that are currently being investigated in clinical trials, and the DAB389IL-2 fusion protein was recently approved for the treatment of refractory MF/SS.

The T-Cell Activation Markers CD30 and OX40/CD134 Are Expressed in Nonoverlapping Subsets of Peripheral T-Cell Lymphoma

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3487-3493 ◽  
Author(s):  
Dan Jones ◽  
Christopher D.M. Fletcher ◽  
Karen Pulford ◽  
Aliakbar Shahsafaei ◽  
David M. Dorfman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Tnf Receptor ◽  
T Cell Lymphomas ◽  
Tumor Types ◽  
Tnf Receptor Family ◽  
Receptor Family

The tumor necrosis factor (TNF) receptor family includes several important markers of activation in T cells. We examined expression patterns of two T-cell-associated members of these receptors, namely CD30 and OX40/CD134, in 148 cases of T-cell lymphoma to identify possible objective immunohistochemical criteria for subclassification of these tumors. CD30 expression was characteristic of tumors with an anaplastic (46/47 cases [98%]) or large-cell (10/21 [48%]) morphology and was seen in only scattered cells in other tumor types. In contrast, large numbers of OX40/CD134+ tumors cells were typical of angioimmunoblastic lymphoma (15/16 [94%]), angiocentric lymphoma (4/4), a subset of large-cell lymphomas (10/21 [48%]), and lymphomas with a prominent histiocytic component (6/7 [86%]). Strong OX40/CD134 and CD30 coexpression was seen in only 4% of tumors, typically those with an anaplastic/Hodgkin’s-like appearance. OX40/CD134 expression was characteristic of tumors composed of activated CD4+ T cells and was not seen in small-cell T-cell lymphomas, lymphoblastic lymphomas, or other tumor types, including B-cell lymphomas or carcinomas. These results suggest that immunostaining for OX40/CD134 may be helpful in subclassification of peripheral T-cell lymphomas and that the patterns of TNF receptor family expression in these tumors may parallel those seen within nonneoplastic helper T-cell subsets.

Brentuximab vedotin in real life, a seven year experience in patients with refractory/relapsed CD30+ T cell lymphoma

2020 ◽  
pp. 107815522096861
Author(s):  
Lucie Oberic ◽  
Faustine Delzor ◽  
Caroline Protin ◽  
Sophie Perriat ◽  
Camille Laurent ◽  
...  
Keyword(s):  
T Cell ◽  
Combination Treatment ◽  
Cell Lymphoma ◽  
Real Life ◽  
Progression Free Survival ◽  
Large Cell ◽  
Complete Response ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
T Cell Lymphomas

Introduction Brentuximab vedotin (Bv) has been approved for the treatment of Refractory/Relapsed (R/R) Anaplastic Large Cell Lymphomas (ALCL) and cutaneous T-Cell Lymphomas, but is also effective in other CD30+ malignancies. We report here the outcomes of patients with various R/R Peripheral T Cell Lymphoma (PTCL) treated with Bv in real life practice. Method This was a retrospective, single-center study based on medical records of patients with R/R PTCL treated either with Bv alone or in combination with chemotherapy. Results Among 27 patients treated with Bv, neutropenia was the main serious adverse event observed in particular when Bv was used as combination treatment. The complete Response Rates (CRR) was 40.7%; it was significantly improved when Bv was used as combination treatment. The majority of eligible patients (7/10) underwent Stem Cell Transplantation. Median Progression Free Survival (PFS) and Overall Survival (OS) were 5.2 months and 12.5 months respectively. Conclusion Our current study shows that Bv used in combination with chemotherapy provides a high CRR and thereby allows SCT in R/R PTCL. The use of Bv treatments in this setting warrants further investigation.

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