ABSTRACT
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other to ultraviolet radiation (UVR). MCPyV-positive and MCPyV-negative MCCs have been considered to be different tumours, as the former harbour few DNA mutations and are not related to UVR, and the latter usually arise in sun-exposed areas and may be found in conjunction with other keratinocytic tumours, mostly squamous cell carcinomas. Two viral oncoproteins, large T antigen (LT; coded by MCPyV_gp3) and small T antigen (sT; coded by MCPyV_gp4), promote different carcinogenic pathways. OBJECTIVES: To determine which genes are differentially expressed in MCPyV-positive and MCPyV-negative MCC; to describe the mutational burden and the most frequently mutated genes in both MCC subtypes; and to identify the clinical and molecular factors that may be related to patient survival. METHODS: Ninety-two patients with a diagnosis of MCC were identified from the medical databases of participating centres. To study gene expression, a customized panel of 172 genes was developed. Gene expression profiling was performed with nCounter technology. For mutational studies, a customized panel of 26 genes was designed. Somatic single nucleotide variants (SNVs) were identified following the GATK Best Practices workflow for somatic mutations. RESULTS: The expression of LT enabled the series to be divided into two groups (LT positive, n = 55; LT negative, n = 37). Genes differentially expressed in LT-negative patients were related to epithelial differentiation, especially SOX9, or proliferation and the cell cycle (MYC, CDK6), among others. Congruently, LT displayed lower expression in SOX9-positive patients, and differentially expressed genes in SOX9-positive patients were related to epithelial/squamous differentiation. In LT-positive patients, the mean SNV frequency was 4.3; in LT-negative patients it was 10 (P = 0.03). On multivariate survival analysis, the expression of SNAI1 [hazard ratio (HR) 1.046, 95% confidence interval (CI) 1.007-1.086; P = 0.02] and CDK6 (HR 1.049, 95% CI 1.020-1.080; P = 0.001) were identified as risk factors. CONCLUSIONS: Tumours with weak LT expression tend to co-express genes related to squamous differentiation and the cell cycle, and to have a higher mutational burden. These findings are congruent with those of earlier studies.
Merkel cell carcinoma (MCC) is an aggressive form of skin tumour. There are two subtypes of MCC: one of them is related to a virus called Merkel cell polyomavirus (MCPyV); the other one is related to persistent exposure to sunlight. The aim of this research was to find differences between these subtypes in their molecular behaviour (the genes that are expressed and the mutations that may be found). To do this, we carried out two studies, one to investigate gene expression (the process cells use to convert the instructions in our DNA into a functional product such as a protein) and one to look at gene mutations (changes in the DNA sequence). We found that the tumours that were not related to MCPyV expressed genes related to epithelial differentiation (the process by which unspecialized cells gain features characteristics of epithelial cells, which, among other things, make up the outer surface of the body), which means that the origin of both MCC subtypes may be different. We also found that MCPyV-related tumours had fewer mutations. Our findings are important because they help us to understand the biology of the MCC subtypes and could help with the development of new treatments for people diagnosed with skin tumours.
Subject(s)
Antigens, Viral, Tumor , Carcinoma, Merkel Cell , Merkel cell polyomavirus , Polyomavirus Infections , SOX9 Transcription Factor , Skin Neoplasms , Tumor Virus Infections , Humans , Carcinoma, Merkel Cell/virology , Carcinoma, Merkel Cell/genetics , Carcinoma, Merkel Cell/pathology , Merkel cell polyomavirus/genetics , Merkel cell polyomavirus/isolation & purification , Skin Neoplasms/virology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Male , Aged , Female , Polyomavirus Infections/genetics , Polyomavirus Infections/virology , Tumor Virus Infections/genetics , Tumor Virus Infections/virology , SOX9 Transcription Factor/genetics , Antigens, Viral, Tumor/genetics , Aged, 80 and over , Middle Aged , Mutation , Gene Expression Regulation, Neoplastic , Gene Expression ProfilingABSTRACT
(A) Correlation matrix of unsupervised co-regulated genes, based on the 208 genes included in the NanoString platform. Some of the clusters of co-regulated genes corresponded to the following: Inflammatory cells; Epstein-Barr virus; B-cells; Cytotoxic T-cells; T-cells; and Proliferation. (B) Analysis of genomic alterations by targeted sequencing. Distribution of mutations in the 62 analyzed genes. Rows correspond to sequenced genes, columns represent individual patients. Color coding: green, missense; blue, synonymous; pink, frameshift; violet, Indel; red, stop gained; yellow, UTR.
Subject(s)
Epstein-Barr Virus Infections , Lymphoma, Extranodal NK-T-Cell , Humans , Herpesvirus 4, Human/genetics , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/pathology , Lymphoma, Extranodal NK-T-Cell/therapy , Mutation , Killer Cells, Natural/pathologyABSTRACT
Primary effusion lymphoma (PEL), Kaposi's sarcoma (KS), and multicentric Castleman's disease (MCD) is an uncommon group of diseases included in the same spectrum with related characteristics. The coexistence of all of them in the same individual is a rare occurrence. We present the case of a 25-year-old patient diagnosed with human immunodeficiency virus (HIV) and the development of all these related pathologies. Despite the use of intensive treatment according to the latest recommendations, the evolution was unfavorable. This case reflects the need for new therapies and research in this field.
Subject(s)
HIV Infections , Herpesvirus 8, Human , Lymphoma, Primary Effusion , Sarcoma, Kaposi , Humans , Adult , Sarcoma, Kaposi/complications , Sarcoma, Kaposi/pathology , Lymphoma, Primary Effusion/complications , Lymphoma, Primary Effusion/diagnosis , HIV Infections/complicationsABSTRACT
ABSTRACT: Primary cutaneous acral CD8-positive T-cell lymphoma consists of slow-growing nodules in acral sites with a histopathology, suggesting high-grade lymphoma despite the indolent clinical course. It has been recently included in WHO-EORTC classification for primary cutaneous lymphomas as a provisional entity. A correct diagnosis of this entity is important because its differential diagnosis include more aggressive cutaneous lymphomas. We present a 53-year-old woman with an indolent solitary nodule on her right leg, which histopathologically showed features of CD8-positive T-cell lymphoma, although with some peculiarities, including epidermotropism, absence of CD68 expression, and positivity for GATA3 and Bcl6 in neoplastic cells. This case could contribute to better define the spectrum of this rare cutaneous lymphoma.
Subject(s)
Biomarkers, Tumor/analysis , CD8-Positive T-Lymphocytes/chemistry , GATA3 Transcription Factor/analysis , Lymphocytes, Tumor-Infiltrating/chemistry , Lymphoma, T-Cell, Cutaneous/chemistry , Proto-Oncogene Proteins c-bcl-6/analysis , Skin Neoplasms/chemistry , Biopsy , CD8-Positive T-Lymphocytes/immunology , Female , Humans , Immunohistochemistry , Lymphocytes, Tumor-Infiltrating/immunology , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Cutaneous/surgery , Middle Aged , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Skin Neoplasms/surgery , Treatment OutcomeABSTRACT
The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject(s)
Genes, Immunoglobulin/genetics , Lymphoma, B-Cell, Marginal Zone/genetics , Complementarity Determining Regions/genetics , Gene Rearrangement, B-Lymphocyte/genetics , Genes, Immunoglobulin Heavy Chain/genetics , Humans , Immunoglobulin Variable Region/genetics , Mutation/genetics , Receptors, Antigen, B-Cell/genetics , Tumor MicroenvironmentABSTRACT
Cutaneous eruption of lymphocyte recovery (ELR) during bone marrow (BM) aplasia recovery after intensive chemotherapy has been reported in very few patients. The presence of skin rashes in patients with acute leukemia who are undergoing intensive chemotherapy and BM transplantation is a diagnostic challenge because of the clinical similarity between drug eruptions, infiltrates related to the relapse of the underlying disease, cutaneous graft-versus-host disease, and ELR. IDH1 mutations have been identified as a recurrent genetic anomaly in acute myeloid leukemia and myelodysplastic syndromes. However, until now, this IDH1 mutation has not been reported as being shared by myeloid cells and non-neoplastic inflammatory cells in this clinical setting. Here, we present the rare case of a woman diagnosed with myelodysplastic syndrome that evolved into an acute myelogenous leukemia with leukemic cutaneous infiltrate. The patient developed ELR after the intensive chemotherapy administered before BM transplantation. The IDH1 mutation was identified in BM cells and in myeloid and inflammatory cells in skin biopsies before allogeneic BM transplantation. We discuss the main aspects of the differential diagnosis of these cutaneous reactions in leukemic patients and the biological significance of the IDH1 mutation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Eruptions/pathology , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Aged , Cytarabine/adverse effects , Female , Humans , Idarubicin/adverse effects , Mutation , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathologyABSTRACT
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways. These results support a driver oncogenic role for VAV1 signaling in the pathogenesis of PTCL.
Subject(s)
Guanine Nucleotide Exchange Factors/genetics , Guanine/metabolism , Lymphoma, T-Cell, Peripheral/genetics , Mutation/genetics , Proto-Oncogene Proteins c-vav/genetics , Translocation, Genetic/genetics , Alternative Splicing/genetics , Amino Acid Sequence , Base Sequence , Cell Line, Tumor , Humans , Jurkat Cells , Sequence Deletion/geneticsABSTRACT
Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS) is a diagnosis of exclusion, showing extreme cytological and phenotypic heterogeneity. Skin involvement of PTCL may be primary or secondary. Diagnosis of histiocytosis may be difficult, requiring clinical-pathological correlation. We describe a laryngeal atypical histiocytic lesion (AHL) and a nasal PTCL, NOS with cutaneous involvement in the same patient presenting with peculiar histopathologic and immunophenotypic features. The laryngeal neoplasm showed morphological and immunophenotypic evidence of histiocytic differentiation and does not fit any other category of the WHO classification nor the revised classification of histiocytosis. The nasal and cutaneous lesions presented features close to natural killer/T-cell lymphoma and gamma-delta T-cell lymphoma but did not meet accurately the WHO criteria. A somatic activating Q61K mutation was found on exon 3 of the NRAS gene in both AHL and PTCL, NOS. The mutation on NRAS gene in both AHL and PTCL, NOS may suggest a common origin from a precursor cell.
Subject(s)
Histiocytosis/pathology , Laryngeal Diseases/pathology , Lymphoma, T-Cell, Peripheral/pathology , Nose Neoplasms/pathology , Skin Neoplasms/pathology , Aged, 80 and over , Female , GTP Phosphohydrolases/genetics , Histiocytosis/genetics , Humans , Laryngeal Diseases/genetics , Lymphoma, T-Cell, Peripheral/genetics , Membrane Proteins/genetics , Mutation , Nose Neoplasms/genetics , Skin Neoplasms/geneticsSubject(s)
AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase/deficiency , Collagen Type I/biosynthesis , DNA Methylation , Hodgkin Disease/enzymology , Neoplasm Proteins/metabolism , RNA Interference , RNA Processing, Post-Transcriptional , RNA, Neoplasm/metabolism , AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase/genetics , AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase/metabolism , Base Sequence , Cell Line, Tumor , Collagen Type I/genetics , Collagen Type I, alpha 1 Chain , CpG Islands/genetics , DNA Methylation/drug effects , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Datasets as Topic , Decitabine/pharmacology , Hodgkin Disease/genetics , Hodgkin Disease/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Lymphocytes/metabolism , Methylation/drug effects , Neoplasm Proteins/genetics , Promoter Regions, Genetic/genetics , RNA Processing, Post-Transcriptional/drug effects , Sequence Alignment , tRNA Methyltransferases/metabolismSubject(s)
Dual-Specificity Phosphatases/genetics , Gene Rearrangement , Lymphoma, Large-Cell, Anaplastic/genetics , Lymphoma, T-Cell, Cutaneous/genetics , Mitogen-Activated Protein Kinase Phosphatases/genetics , Mycosis Fungoides/genetics , Skin Neoplasms/genetics , Skin/pathology , Aged , Humans , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, T-Cell, Cutaneous/pathology , Male , Mycosis Fungoides/pathology , Skin Neoplasms/pathologyABSTRACT
Follicular helper T-cells (TFH) represent a specific subset of CD4-positive helper T-cells that help B-cells to differentiate into long-lived antibody-secreting plasma cells or memory B-cells. The expression of TFH markers in neoplastic T-cells, traditionally related to the angioimmunoblastic (AITL) subgroup of peripheral T-cell lymphomas, is nowadays well-known to be more widespread than previously thought. We report hereby a case of cutaneous T-cell lymphoma in a 75-year-old woman, whose morphological and immunophenotypical features raises the differential diagnosis between cutaneous involvement by AITL and the recently described primary cutaneous T-cell lymphoma with follicular helper-phenotype.
Subject(s)
Lymphoma, Follicular , Lymphoma, T-Cell, Cutaneous , Lymphoma, T-Cell, Peripheral , Skin Neoplasms , T-Lymphocytes, Regulatory , Aged , Female , Humans , Lymphoma, Follicular/immunology , Lymphoma, Follicular/metabolism , Lymphoma, Follicular/pathology , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/metabolism , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Peripheral/immunology , Lymphoma, T-Cell, Peripheral/metabolism , Lymphoma, T-Cell, Peripheral/pathology , Skin Neoplasms/immunology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/pathologySubject(s)
Gene Rearrangement , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/etiology , Phenotype , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-myc/genetics , Skin Neoplasms/diagnosis , Skin Neoplasms/etiology , Aged, 80 and over , Biopsy , Female , Genetic Association Studies , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Immunophenotyping , In Situ Hybridization, FluorescenceABSTRACT
SPIB is an Ets transcription factor that is expressed exclusively in mature B cells, T-cell progenitors, and plasmacytoid dendritic cells. In the present study, we developed a novel mAb against the SPIB protein and characterized its expression in major hematolymphoid neoplasms, including a series of 45 cases of blastic plasmacytoid dendritic cell (BPDC) neoplasms and their potential cutaneous mimics. We found that SPIB is expressed heterogeneously among B- and T-cell lymphoma types. Interestingly, SPIB is expressed in a large proportion of nongerminal center type DLBCLs. In cutaneous neoplasms, SPIB is overexpressed in all BPDC neoplasms, but none of its cutaneous mimics. SPIB remains overexpressed in all cases that lack 1 or 2 of the markers used for BPDC neoplasms (ie, CD4, CD56, TCL1, and CD123). We conclude that SPIB expression can be used as a tool for diagnosing BPDC neoplasms, but it needs to be tested in conjunction with the growing arsenal of markers for human plasmacytoid dendritic cells.
Subject(s)
Biomarkers, Tumor/metabolism , DNA-Binding Proteins/metabolism , Dendritic Cells/metabolism , Hematologic Neoplasms/metabolism , Transcription Factors/metabolism , Biomarkers, Tumor/genetics , Cell Line, Tumor , DNA-Binding Proteins/genetics , Dendritic Cells/pathology , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Humans , Lymphoid Tissue/metabolism , Lymphoid Tissue/pathology , Lymphoma/diagnosis , Lymphoma/genetics , Lymphoma/metabolism , Transcription Factors/geneticsSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Follicular/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Abnormal Karyotype , Antigens, Neoplasm/analysis , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Asparaginase/administration & dosage , Biomarkers, Tumor/analysis , Biopsy , Cyclophosphamide/administration & dosage , DNA Nucleotidylexotransferase/analysis , Disease Progression , Doxorubicin/administration & dosage , Fatal Outcome , Female , Humans , Lymphoma, Follicular/drug therapy , Mercaptopurine/administration & dosage , Methotrexate/administration & dosage , Middle Aged , Pancytopenia/etiology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prednisone/administration & dosage , Recurrence , Rituximab/administration & dosage , Salvage Therapy , Splenic Rupture/etiology , Splenomegaly/etiology , Stomach/pathology , Vincristine/administration & dosageSubject(s)
Cyclin D3/genetics , Cyclin D3/metabolism , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/metabolism , Mutation , Splenic Neoplasms/genetics , Splenic Neoplasms/metabolism , Gene Expression , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Lymphoma, B-Cell/pathology , Splenic Neoplasms/pathologyABSTRACT
AIMS: Immunoglobulin light-chain expression is used routinely as an indirect marker of clonality for recognizing B cell lymphoproliferative disorders. METHODS AND RESULTS: Here we describe four floral follicular hyperplasia cases in the gastrointestinal tract (appendix and rectum) of children (4 to 6 years). Immunohistochemical studies revealed lambda light-chain restriction that was associated with polyclonal IgH pattern. Clinical features and follow-up of the patients did not reveal any other systemic symptoms, laboratory abnormalities or organ alterations. CONCLUSIONS: Recognition of this phenomenon is useful in the diagnosis of nodular lymphoid hyperplasia of the gastrointestinal tract, for avoiding overdiagnosis of lymphoid malignancies, and raises concerns that the identification of light-chain restriction is not necessarily a marker of monoclonality.
Subject(s)
Appendix/pathology , Immunoglobulin Light Chains , Lymphoproliferative Disorders/pathology , Rectum/pathology , Child , Child, Preschool , Female , Humans , Hyperplasia/immunology , Hyperplasia/pathology , Immunohistochemistry , In Situ Hybridization, Fluorescence , Lymphoproliferative Disorders/immunology , Male , Multiplex Polymerase Chain ReactionSubject(s)
Lymphoma, Follicular , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Diagnosis, Differential , Female , Humans , Lymphoma, Follicular/diagnosis , Lymphoma, Follicular/metabolism , Lymphoma, Follicular/pathology , Middle Aged , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.