ABSTRACT
Proteasome inhibitor (PI) therapy has improved the survival of multiple myeloma (MM) patients. However, inevitably, primary or acquired resistance to PIs leads to disease progression; resistance mechanisms are unclear. Obesity is a risk factor for MM mortality. Oxidized LDL (OxLDL), a central mediator of atherosclerosis that is elevated in metabolic syndrome (co-occurrence of obesity, insulin resistance, dyslipidemia and hypertension), has been linked to an increased risk of solid cancers and shown to stimulate pro-oncogenic/survival signaling. We hypothesized that OxLDL is a mediator of chemoresistance and evaluated its effects on MM cell killing by PIs. OxLDL potently suppressed the ability of the boronic acid-based PIs bortezomib (BTZ) and ixazomib, but not the epoxyketone-based PI carfilzomib, to kill human MM cell lines and primary cells. OxLDL suppressed BTZ-induced inhibition of proteasome activity and induction of pro-apoptotic signaling. These cytoprotective effects were abrogated when lipid hydroperoxides (LOOHs) associated with OxLDL were enzymatically reduced. We also demonstrated the presence of OxLDL in the MM bone marrow microenvironment as well as numerous granulocytes and monocytes capable of cell-mediated LDL oxidation through myeloperoxidase. Our findings suggest that OxLDL may be a potent mediator of boronic acid-based PI resistance, particularly for MM patients with metabolic syndrome, given their elevated systemic levels of OxLDL. LDL cholesterol-lowering therapy to reduce circulating OxLDL, and pharmacologic targeting of LOOH levels or resistance pathways induced by the modified lipoprotein, could deepen the response to these important agents and offer clinical benefit to MM patients with metabolic syndrome.
Subject(s)
Drug Resistance, Neoplasm , Lipoproteins, LDL/metabolism , Multiple Myeloma/metabolism , Proteasome Inhibitors/pharmacology , Boron Compounds/pharmacology , Bortezomib/pharmacology , Cell Line, Tumor , Glycine/analogs & derivatives , Glycine/pharmacology , Granulocytes/metabolism , Humans , Lipid Peroxides/metabolism , Monocytes/metabolism , Multiple Myeloma/drug therapy , Oligopeptides/pharmacology , Proteasome Inhibitors/therapeutic useABSTRACT
Much-needed attention has been given of late to diseases specifically associated with an expanding elderly population. Myelodysplastic syndrome (MDS), a hematopoietic stem cell-based blood disease, is one of these. The lack of clear understanding of the molecular mechanisms underlying the pathogenesis of this disease has hampered the development of efficacious therapies, especially in the presence of comorbidities. Mouse models could potentially provide new insights into this disease, although primary human MDS cells grow poorly in xenografted mice. This makes genetically engineered murine models a more attractive proposition, although this approach is not without complications. In particular, it is unclear if or how myelodysplasia (abnormal blood cell morphology), a key MDS feature in humans, presents in murine cells. Here, we evaluate the histopathologic features of wild-type mice and 23 mouse models with verified myelodysplasia. We find that certain features indicative of myelodysplasia in humans, such as Howell-Jolly bodies and low neutrophilic granularity, are commonplace in healthy mice, whereas other features are similarly abnormal in humans and mice. Quantitative hematopoietic parameters, such as blood cell counts, are required to distinguish between MDS and related diseases. We provide data that mouse models of MDS can be genetically engineered and faithfully recapitulate human disease.
Subject(s)
Disease Models, Animal , Genetic Engineering , Hematopoietic Stem Cells/pathology , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Animals , Hematopoiesis , Humans , Mice , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/diagnosisABSTRACT
Follicular dendritic cell (FDC) proliferations and dysplastic FDCs can be seen in Hyaline-vascular Castleman disease (HVCD). The association between HVCD and FDC sarcoma is well-documented; dysplastic FDCs may be precursors to FDC sarcoma. Herein, we describe a case of HVCD with strikingly large and dysplastic FDCs, which raised the differential of Hodgkin lymphoma and other neoplasms. Scattered dysplastic FDCs were predominantly in germinal centers and mantle zones, and rarely in interfollicular areas. Although occasional germinal centers contained increased FDCs, no mass forming proliferations were present to suggest FDC sarcoma. Immunostaining demonstrated that the atypical FDCs expressed CD21, clusterin and CXCL13, but not CD23, S100, pankeratin or CD30; they aberrantly expressed epidermal growth factor receptor (EGFR). The present case demonstrates that dysplastic FDCs may be present as isolated cells that require immunophenotyping to distinguish them from malignant entities with similar morphologic features. A variety of FDC markers is required to confirm their origin as the expression of any single marker is not assured, as occurred in this case. Pathologists need be aware of FDC proliferations in HVCD because of their association with FDC sarcoma. Aberrant EGFR expression by dysplastic FDCs may indicate that they are pre-neoplastic and necessitate long-term patient follow-up.
Subject(s)
Castleman Disease/diagnosis , Castleman Disease/pathology , Dendritic Cells, Follicular/pathology , Adult , Biomarkers/analysis , Diagnosis, Differential , Female , Hodgkin Disease/diagnosis , Humans , Hyalin/metabolism , ImmunohistochemistryABSTRACT
The characterization of immunoglobulin heavy chain (IGH) translocations provides information on the diagnosis and guides therapeutic decisions in mature B-cell malignancies while enhancing our understanding of normal and malignant B-cell biology. However, existing methodologies for the detection of IGH translocations are labor intensive, often require viable cells, and are biased toward known IGH fusions. To overcome these limitations, we developed a capture sequencing strategy for the identification of IGH rearrangements at nucleotide level resolution and tested its capabilities as a diagnostic and discovery tool in 78 primary diffuse large B-cell lymphomas (DLBCLs). We readily identified IGH-BCL2, IGH-BCL6, IGH-MYC, and IGH-CCND1 fusions and discovered IRF8, EBF1, and TNFSF13 (APRIL) as novel IGH partners in these tumors. IRF8 and TNFSF13 expression was significantly higher in lymphomas with IGH rearrangements targeting these loci. Modeling the deregulation of IRF8 and EBF1 in vitro defined a lymphomagenic profile characterized by up-regulation of AID and/or BCL6, down-regulation of PRMD1, and resistance to apoptosis. Using a capture sequencing strategy, we discovered the B-cell relevant genes IRF8, EBF1, and TNFSF13 as novel targets for IGH deregulation. This methodology is poised to change how IGH translocations are identified in clinical settings while remaining a powerful tool to uncover the pathogenesis of B-cell malignancies.
Subject(s)
Immunoglobulin Heavy Chains/genetics , Interferon Regulatory Factors/genetics , Lymphoma, B-Cell/genetics , Oncogene Proteins, Fusion/genetics , Trans-Activators/genetics , Tumor Necrosis Factor Ligand Superfamily Member 13/genetics , Base Sequence , Cell Line, Tumor , Gene Library , Gene Rearrangement, B-Lymphocyte/genetics , HEK293 Cells , High-Throughput Nucleotide Sequencing/methods , Humans , Interferon Regulatory Factors/physiology , Molecular Sequence Data , Trans-Activators/physiology , Tumor Necrosis Factor Ligand Superfamily Member 13/physiology , Validation Studies as TopicABSTRACT
BACKGROUND: Optimal therapy for children and adolescents with advanced stage anaplastic large cell lymphoma (ALCL) is unknown. ANHL0131 examined whether a maintenance regimen including vinblastine compared to the standard APO (doxorubicin, prednisone, vincristine, methotrexate, 6-mercaptopurine) regimen would result in superior event-free survival. PROCEDURE: One hundred and twenty five eligible patients were enrolled. Induction was identical for both arms. Post induction patients were randomized to receive APO with vincristine every 3 weeks or a regimen that substituted vincristine with weekly vinblastine (APV). RESULTS: There was no difference between the patients randomized to the APO versus APV arms in either event free survival (EFS) or overall survival (OS) (three year EFS 74% vs. 79%, P = 0.68 and three years OS of 84% vs. 86%, P = 0.87, respectively). Patients in the APV arm required dose reduction secondary to myelosuppression and had a higher incidence of neutropenia as well as infection with neutropenia compared to those in the APO arm (P < 0.001, P = 0.019, respectively). CONCLUSIONS: Treatment with weekly vinblastine instead of every three week vincristine as part of multi-agent maintenance therapy did not result in improvement in EFS or OS. Weekly vinblastine was associated with increased toxicity. (ClinicalTrials.gov Identifier NCT00059839).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large-Cell, Anaplastic/drug therapy , Adolescent , Adult , Child , Child, Preschool , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Infant , Lymphoma, Large-Cell, Anaplastic/mortality , Lymphoma, Large-Cell, Anaplastic/pathology , Male , Mercaptopurine/administration & dosage , Methotrexate/administration & dosage , Neoplasm Staging , Prednisone/administration & dosage , Prognosis , Survival Rate , Vinblastine/administration & dosage , Vincristine/administration & dosage , Young AdultABSTRACT
Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL(ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA-sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by diferential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK- high group, which had more frequent copy number changes, and was enriched with pathways associated with cell growth, proliferation, metabolic pathways, and. Taken together, these findings suggest that there is molecular heterogeneity within pediatric ALK+ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.
ABSTRACT
Anaplastic large cell lymphomas (ALCL) are mature T-cell neoplasms, approximately half of which harbor rearrangements of the ALK gene that confer a good prognosis. Recent studies have demonstrated that a significant proportion of ALK-negative ALCLs demonstrate rearrangements of the IRF4/DUSP22 locus that also are typically associated with a favorable prognosis. ALCL with primary involvement of the central nervous system (CNS) is extremely rare. We report what may be the first case of ALK-negative ALCL with IRF4/DUSP22 rearrangement involving the brain in a 55-year-old man. Magnetic resonance imaging demonstrated signal abnormalities in the periventricular region, corpus callosum and cingulate gyrus. Biopsy revealed a diffuse parenchymal and angiocentric infiltrate of CD30-positive cells that showed IRF4/DUSP22 rearrangement by fluorescence in situ hybridization. We also review the clinical and pathologic features of primary CNS ALK-negative ALCLs in the literature and highlight the need for awareness of this entity to optimize appropriate management.
Subject(s)
Lymphoma, Large-Cell, Anaplastic , Central Nervous System , Dual-Specificity Phosphatases , Gene Rearrangement , Humans , In Situ Hybridization, Fluorescence , Lymphoma, Large-Cell, Anaplastic/diagnosis , Lymphoma, Large-Cell, Anaplastic/genetics , Male , Middle Aged , Mitogen-Activated Protein Kinase Phosphatases , Receptor Protein-Tyrosine Kinases/geneticsABSTRACT
MicroRNA (miRNA) deregulation contributes to cancer pathogenesis. However, analysis of miRNAs in diffuse large B-cell lymphoma (DLBCL) has been hindered by a focus on cell lines, limited number of miRNAs examined, and lack of copy number data. To address these restrictions, we investigated genomewide miRNA expression and copy number data in 86 DLBCLs. Permutation analysis showed that 63 miRNAs were recurrently disrupted in DLBCL, including highly expressed oncomirs not previously linked to chromosomal abnormalities. Further, using training and validation tumor groups, we defined a collection of miRNAs that robustly segregates DLBCLs into 3 subsets, which are independent of the cell-of-origin classification, extent of T-cell infiltrate, and tumor site. Instead, these unique miRNA-driven DLBCL subgroups showed markedly different MYC transcriptional activity, which explained the dominance of miRNAs regulated by MYC in their expression signatures. In addition, analysis of miRNA expression patterns of normal B cells and integration of copy number and expression data showed that genomic abnormalities and the genetic fingerprint of nonmalignant cells also contribute to the miRNA profile of DLBCL. In conclusion, we created a comprehensive map of the miRNA genome in DLBCL and, in the process, have uncovered and mechanistically elucidated the basis for additional molecular heterogeneity in this tumor.
Subject(s)
B-Lymphocytes/metabolism , Gene Dosage , Gene Expression Profiling , Genes, myc , Lymphoma, Large B-Cell, Diffuse/genetics , MicroRNAs/biosynthesis , RNA, Neoplasm/biosynthesis , Gene Expression Regulation, Neoplastic , Genetic Heterogeneity , Genome-Wide Association Study , Humans , Lymphoma, Large B-Cell, Diffuse/metabolism , MicroRNAs/genetics , RNA, Neoplasm/genetics , Transcription, GeneticABSTRACT
In mature B-cell malignancies, chromosomal translocations often juxtapose an oncogenic locus to the regulatory regions of the immunoglobulin genes. These genomic rearrangements can associate with specific clinical/pathological sub-entities and inform diagnosis and treatment decisions. Recently, we characterized the t(14;16)(q32;q24) in diffuse large B-cell lymphoma (DLBCL), and showed that it targets the transcription factor IRF8, which is also somatically mutated in ~10% of DLBCLs. IRF8 regulates innate and adaptive immune responses mediated by myeloid/monocytic and lymphoid cells. While the role of IRF8 in human myeloid/dendritic-cell disorders is well established, less is known of its contribution to the pathogenesis of mature B-cell malignancies. To address this knowledge gap, we generated the Eµ-Irf8 mouse model, which mimics the IRF8 deregulation associated with t(14;16) of DLBCL. Eµ-Irf8 mice develop normally and display peripheral blood cell parameters within normal range. However, Eµ-Irf8 mice accumulate pre-pro-B-cells and transitional B-cells in the bone marrow and spleen, respectively, suggesting that the physiological role of Irf8 in B-cell development is amplified. Notably, in Eµ-Irf8 mice, the lymphomagenic Irf8 targets Aicda and Bcl6 are overexpressed in mature B-cells. Yet, the incidence of B-cell lymphomas is not increased in the Eµ-Irf8 model, even though their estimated survival probability is significantly lower than that of WT controls. Together, these observations suggest that the penetrance on the Irf8-driven phenotype may be incomplete and that introduction of second genetic hit, a common strategy in mouse models of lymphoma, may be necessary to uncover the pro-lymphoma phenotype of the Eµ-Irf8 mice.
Subject(s)
Immunoglobulin Heavy Chains/genetics , Interferon Regulatory Factors/genetics , Lymphoma, B-Cell/mortality , Oncogene Proteins, Fusion/genetics , Animals , Disease Models, Animal , Enhancer Elements, Genetic , Female , Humans , Lymphoma, B-Cell/genetics , Male , Mice , Survival AnalysisABSTRACT
The recent development of inhibitors of key immune response proteins has revolutionized the therapy of autoimmune diseases; these immunomodulator agents include monoclonal antibodies and receptor antagonists. However, as with all therapies, these new agents are not without side effects and complications. In particular, anti-tumor necrosis factor alpha (TNFalpha) agents have been reported to be associated with an increased incidence of lymphoproliferative disorders, infections, and vasculitis. We evaluated the clinicopathological features of 18 cases of immunomodulator agent-related lymphoproliferative disorders (IAR-LPD) from several institutions. These included 6 cases of B-cell lymphoma, 2 cases of T-cell lymphoma, 3 cases of classical Hodgkin lymphoma, and 7 atypical lymphoid proliferations that did not fulfill diagnostic criteria for lymphoma; two of the latter regressed after discontinuation of the immunomodulator agent therapy. All eight lymphoma patients with available information had also received prior chemotherapy (methotrexate or 6-mercaptopurine). EBV was strongly associated with the B-cell and classical Hodgkin lymphomas. This case series illustrates that a broad range of lymphoid proliferations can occur after immunomodulator agent therapy and that these immunomodulator agent-related lymphoproliferative disorders have considerable overlap with other well-defined lymphoproliferative diseases associated with iatrogenic immunosuppression. Further study is warranted to evaluate how these therapies interact with other immunosuppressive agents and the underlying abnormal immune system to enhance the development of lymphomas and atypical lymphoid proliferations.
Subject(s)
Autoimmune Diseases/drug therapy , Iatrogenic Disease , Immunologic Factors/adverse effects , Lymphoproliferative Disorders/chemically induced , Adult , Aged , Antineoplastic Agents/therapeutic use , Autoimmune Diseases/immunology , Belgium , Female , Herpesvirus 4, Human/isolation & purification , Hodgkin Disease/chemically induced , Humans , Immunosuppressive Agents/adverse effects , Lymphoma, B-Cell/chemically induced , Lymphoma, T-Cell/chemically induced , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/pathology , Lymphoproliferative Disorders/virology , Male , Middle Aged , Treatment Outcome , United States , Young AdultABSTRACT
Early diagnosis of invasive pulmonary aspergillosis is problematic in some patient groups due to the lack of rapid, sensitive, specific, and reliable diagnostic tests. Fungal burden and therapeutic efficacy were assessed by survival, quantitative culture (CFU counts), galactomannan enzyme immunoassay (GM-EIA), and quantitative PCR (qPCR) in a new guinea pig model of invasive pulmonary aspergillosis using an aerosol challenge. At 1 day postinfection, qPCR determined that the pulmonary fungal burden was 2 log(10) higher than that determined by CFU counting and increased significantly (P < 0.03) over time. In contrast, the tissue burden assessed by CFU counting did not rise over the course of the study. Therapy with the antifungal drug voriconazole produced statistically significant decreases in pulmonary fungal burden, as detected by CFU counting (P < 0.02), qPCR, and GM-EIA (both P < 0.0002). Daily assessment of the progression of fungal infection in serum was performed by qPCR and GM-EIA. GM-EIA demonstrated a statistically significant reduction in the fungal load on days 6 and 7 in voriconazole-treated animals compared to time-matched controls (P < 0.02). Confirmation of fungal tissue burden by two or more methods should provide a more precise account of the burden, allowing improved assessment of diagnostic and therapeutic strategies in invasive pulmonary aspergillosis.
Subject(s)
Aspergillosis/diagnosis , Aspergillus fumigatus/isolation & purification , Lung Diseases, Fungal/diagnosis , Animals , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillus fumigatus/chemistry , Aspergillus fumigatus/genetics , Base Sequence , Colony Count, Microbial , DNA Primers/genetics , DNA, Fungal/genetics , Disease Models, Animal , Galactose/analogs & derivatives , Guinea Pigs , Humans , Immunoenzyme Techniques/methods , Lung/microbiology , Lung/pathology , Lung Diseases, Fungal/drug therapy , Lung Diseases, Fungal/microbiology , Male , Mannans/analysis , Mycology/methods , Polymerase Chain Reaction/methods , Pyrimidines/therapeutic use , Triazoles/therapeutic use , VoriconazoleABSTRACT
Cases drawn from Session 5 of the 2005 Society for Hematopathology/European Association for Haematopathology Workshop on progress in T-cell and natural killer (NK)-cell malignancies are used as a framework to review the current classification of T-cell and NK-cell malignancies in skin. In comparison with the typical pattern and course of mycosis fungoides (MF), selected variants of MF that can be difficult to diagnose are discussed. Cutaneous CD30+ lymphoproliferative disorders are also presented in detail. Particular focus is placed on the recognition of rare but clinically more aggressive cytotoxic lymphomas in the skin. Overall, diagnostic pitfalls and new information regarding disease pathogenesis brought up by the Workshop cases are provided. In addition, a general approach to the diagnosis of cutaneous T-cell lymphomas is discussed.
Subject(s)
Killer Cells, Natural/pathology , Lymphoma, T-Cell, Cutaneous/classification , Skin Neoplasms/classification , Humans , Ki-1 Antigen/analysis , Lymphoma, T-Cell, Cutaneous/diagnosis , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoproliferative Disorders/classification , Mycosis Fungoides/classification , Mycosis Fungoides/pathology , Skin Neoplasms/diagnosis , Skin Neoplasms/pathology , World Health OrganizationABSTRACT
CD56 (NCAM), a neural adhesion molecule, is normally expressed on natural killer cells and subsets of T cells and is commonly seen on hematolymphoid neoplasms such as plasma cell myeloma and acute myelogenous leukemia. It is uncommon in B-cell lymphoma. From 2001 to 2003 a cohort of 20 cases of CD56 B-cell lymphomas was identified by flow cytometry (<0.5% of all B-cell lymphomas studied) during a 2-year period. Most (90%) expressed CD10 and 5/5 tested cases were BCL6, suggesting a follicular origin. An extranodal disease presentation was seen in 45% and may be related to CD56 expression. These CD56 B-cell lymphomas may represent a new subset of large B-cell lymphoma. The relationship of cells with this antigenic profile to normal B-cell differentiation is explored.
Subject(s)
CD56 Antigen/metabolism , Lymphoma, B-Cell/pathology , Adult , Aged , Aged, 80 and over , Female , Flow Cytometry , Humans , Immunohistochemistry , Immunophenotyping , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/metabolism , Male , Middle AgedABSTRACT
Perturbations in CREB binding protein (CREBBP) are associated with hematopoietic malignancies, including myelodysplastic syndrome (MDS). Mice hemizygous for Crebbp develop myelodysplasia with proliferative features, reminiscent of human MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U), and a proportion goes on to develop acute myeloid leukemia (AML). We have also shown that the Crebbp+/- non-hematopoietic bone marrow microenvironment induces excessive myeloproliferation of wild-type cells. We now report that transplantation of unfractionated Crebbp+/- bone marrow into wild-type recipients resulted in either early-onset AML or late-onset MDS and MDS/MPN-U. In contrast, purified Lin-Sca-1+c-Kit++ cells primarily gave rise to MDS with occasional transformation to AML. Furthermore, Crebbp+/- common myeloid progenitors and granulocyte/macrophage progenitors could trigger skewed myelopoiesis, myelodysplasia and late-onset AML. Surprisingly, the phenotypically abnormal cells were all of wild-type origin. MDS, MPN and AML can thus all be transferred from Crebbp+/- BM to wild-type hosts but fractionated bone marrow does not recapitulate the full disease spectrum of whole bone marrow, indicating that not only mutational status but also cellular context contribute to disease outcome. This has important consequences for structuring and interpreting future investigations into the underlying mechanisms of myeloid malignancies as well as for their treatment.
Subject(s)
Bone Marrow/pathology , CREB-Binding Protein/genetics , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Animals , Bone Marrow/metabolism , Cytokines/genetics , Gene Expression Regulation, Neoplastic , Hematopoiesis , Hemizygote , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Matrix Metalloproteinase 9/genetics , Mice , Mice, Inbred C57BL , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathologyABSTRACT
Anaplastic large cell lymphoma (ALCL) is an aggressive large T- or null-cell lymphoma. Most ALCLs arising in children and young adults express a constitutively active receptor tyrosine kinase, anaplastic lymphoma kinase (ALK). Anaplastic large cell lymphomas lacking ALK are clinically heterogeneous and their pathogenesis is unknown. This study is the first complementary DNA (cDNA) microarray analysis using RNA extracted from tumor tissue (7 ALK+ ALCLs and 7 ALK- ALCLs) to identify genes differentially expressed or shared between the ALK+ and ALK- tumors. Unsupervised hierarchical clustering using the top 11 most statistically significant discriminator cDNAs correctly grouped all ALK+ and ALK- tumors. Hierarchical clustering analysis using the 44 cDNAs with the greatest differential expression between ALK+ and ALK- RNAs grouped 6 of 7 ALK+ ALCLs together and 1 ALK+ ALCL with the ALK- group. In general, ALK+ tumors overexpress genes encoding signal transduction molecules (SYK , LYN , CDC37) and underexpress transcription factor genes (including HOXC6 and HOX A3 ) compared with the ALK- group. Cyclin D3 was overexpressed in the ALK+ group and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of promoting G 1 /S transition. Both groups had similar proliferation rates. Genes highly expressed in both ALK- and ALK+ ALCLs included kinases (LCK, protein kinase C, vav2, and NKIAMRE) and antiapoptotic molecules, suggesting possible common pathogenetic mechanisms as well.
Subject(s)
Gene Expression , Lymphoma, Large B-Cell, Diffuse/enzymology , Lymphoma, Large B-Cell, Diffuse/genetics , Protein-Tyrosine Kinases/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Child , Cyclin D3 , Cyclin-Dependent Kinase Inhibitor p19 , Cyclins/genetics , Cyclins/metabolism , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Receptor Protein-Tyrosine Kinases , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
PURPOSE: To assess the accuracy of 2-Deoxy-2-[F-18] Fluoro-D-Glucose positron emission imaging (FDG-PET) for staging Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) compared to conventional staging (CS) and to evaluate the impact on patient management. METHODS: Forty-five consecutive patients with lymphoma underwent whole-body FDG-PET imaging for initial staging. Discordant lesions were verified with biopsy or clinical follow-up. The impact on staging and management was reviewed retrospectively. RESULTS: A total of 129 sites of disease were identified, and 88 of those were concordant. FDG-PET and conventional staging demonstrated 24 and 17 additional sites, respectively. FDG-PET correctly upstaged five patients and down-staged two patients (16% total), leading to a change in therapy in 6/45 (13%) patients. However, FDG-PET understaged three patients (7%), correctly staged by conventional staging modalities. Assuming that the addition of FDG-PET to conventional staging modalities is 100% accurate for staging lymphoma, the accuracy of FDG-PET alone was 91%, compared to 84% for conventional staging modalities. CONCLUSIONS: FDG-PET is a noninvasive and efficient imaging modality for staging patients with lymphoma and should be used in conjunction with conventional staging modalities, as they appear complementary.
ABSTRACT
The purpose of this study was to better define the clinical features and natural history of peripheral T-cell lymphomas (PTCL) entities included in the Revised European American lymphoma (REAL) classification. Cases of PTCL were retrieved from the records of the Department of Pathology and classified according to the REAL classification. In addition, cases of anaplastic large cell lymphoma (ALCL) were divided into classical, small cell, and primary cutaneous subtypes, and immunostaining for the anaplastic large-cell kinase (ALK) protein was performed on all cases of ALCL. Clinical features, response to therapy and survival were abstracted. Ninety-two cases of PTCL with adequate clinical information were retrieved. There were 40 cases of ALCL (30 classical, 7 small cell variant, 3 primary cutaneous), 28 PTCL, unspecified, 13 angioimmunoblastic T-cell lymphoma and 11 with other entities. The patients had a median age of 48 years with a range of 6-84 and had an estimated overall survival (OS) of 49% and progression-free survival (PFS) of 22% at 5 years. The International Prognostic Index (IPI) was a significant prognostic factor for both progression-free and OS. Histology was a significant predictor of PFS with anaplastic large cell having the best prognosis. ALK expression was not associated with an improved progression-free or overall-survival in patients with systemic T-cell ALCL. In conclusion, the REAL classification describes distinct PTCL entities. The IPI is the most important predictor of progression-free and OS in patients with PTCL. ALK expression may not provide prognostic information for systemic ALCL.
Subject(s)
Lymphoma, T-Cell, Peripheral/classification , Lymphoma, T-Cell, Peripheral/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Immunoblastic Lymphadenopathy/classification , Immunoblastic Lymphadenopathy/mortality , Immunoblastic Lymphadenopathy/pathology , Lymphoma, Large B-Cell, Diffuse/classification , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, T-Cell, Peripheral/diagnosis , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Analysis , Survival Rate , Treatment OutcomeABSTRACT
Session 1 of the 2011 Workshop of the Society for Hematopathology and European Association for Haematopathology focused on mycosis fungoides (MF), the most common cutaneous lymphoma. The 62 cases in this case group demonstrated a wide spectrum of clinicopathologic features, including those seen in typical cases as well as those, by contrast, with atypical clinical history, morphology, immunophenotype, and/or genotype. Of the 62 cases, 27 (44%) were presented at the workshop and highlighted diagnostic challenges plus related issues. This report summarizes the approach recommended for making a confident diagnosis of MF and its clinically significant variants; emphasizes pitfalls in evaluating early MF, assessing nodal involvement, and diagnosing transformed MF; and discusses the relationship between MF and primary cutaneous CD30+ T-cell lymphoproliferative disorders. Last, Sézary syndrome is discussed, with concentration on those features distinct from MF.
Subject(s)
Mycosis Fungoides/diagnosis , Skin Neoplasms/diagnosis , HumansABSTRACT
Primary cutaneous T-cell lymphomas (CTCL) excluding mycosis fungoides (MF) were discussed in 2 sessions of the 2011 Society for Hematopathology/ European Association of Haematopathology Workshop, Los Angeles, CA. Session 2 focused on primary cutaneous CD30+ T-cell lymphoproliferative disorders and their differential diagnosis, including systemic CD30+ T-cell lymphoma secondarily infiltrating the skin. Interesting features like special morphologic variants and atypical phenotypes were presented. In addition, the possibility of rare ALK+ primary cutaneous lymphomas was discussed. Session 3 examined other more uncommon non-MF CTCLs, including subcutaneous panniculitis-like T-cell lymphoma, extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and rare subtypes of primary cutaneous peripheral T-cell lymphoma, not otherwise specified. In addition, systemic T-cell lymphomas involving the skin secondarily, such as angioimmunoblastic T-cell lymphoma, were included in this session. In this report, novel findings, areas of special interest, and diagnostic challenges emerging from the cases submitted to the workshop will be highlighted. The necessity to integrate histologic, immunophenotypical, genetic, and in particular, clinical data to arrive at the correct diagnosis, and subsequently provide adequate treatment, is emphasized.
Subject(s)
Lymphoma, T-Cell, Cutaneous/diagnosis , Skin Neoplasms/diagnosis , HumansABSTRACT
The diagnosis and classification of the cutaneous B-cell lymphomas can be quite a challenge, with a definitive diagnosis sometimes being elusive, even when an extensive workup has been performed. Distinction of benign from neoplastic disorders can be difficult, with some hyperplasias mimicking lymphomas and vice versa. There are only a limited number of skin-specific B-cell lymphomas, including primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous marginal zone lymphomas have distinctive features but are classified with the other mucosa-associated lymphoid tissue lymphomas. It is important, however, to also remember that many other B-cell lymphomas/ plasma cell neoplasms can primarily, or more often secondarily, involve the skin. Some may mimic one of the skin-specific lymphomas but have very different clinical implications. Iatrogenic and senescent immunodeficiency-associated lymphoproliferative disorders that are often Epstein-Barr virus (EBV) positive can also primarily involve the skin, including cases also known as EBV-positive mucocutaneous ulcer.