Subject(s)
B7-H1 Antigen/immunology , Central Nervous System Neoplasms/immunology , Lymphoma, B-Cell/immunology , Major Histocompatibility Complex , Programmed Cell Death 1 Ligand 2 Protein/immunology , Testicular Neoplasms/immunology , Aged , Aged, 80 and over , B7-H1 Antigen/genetics , Central Nervous System Neoplasms/genetics , Female , Gene Deletion , Genes, MHC Class I , Genes, MHC Class II , Humans , Immune Evasion , Lymphoma, B-Cell/genetics , Male , Middle Aged , Mutation , Programmed Cell Death 1 Ligand 2 Protein/genetics , Testicular Neoplasms/geneticsABSTRACT
The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of DLBCL, however, is characterized by activating mutations in MYD88/CD79B We investigated whether MYD88/CD79B mutations could improve the classification and prognostication of DLBCL. In 250 primary DLBCL, MYD88/CD79B mutations were identified by allele-specific polymerase chain reaction or next-generation-sequencing, MYC/BCL2/BCL6 rearrangements were analyzed by fluorescence in situ hybridization, and EBV was studied by EBV-encoded RNA in situ hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. MYD88 and CD79B mutations were identified in 29.6% and 12.3%, MYC, BCL2, and BCL6 rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and MYD88/CD79B mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. MYD88-mutated DLBCL had a significantly inferior 5-year overall survival than wild-type MYD88 DLBCL (log-rank; P=0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases carrying ≥1 aberrancy (log-rank; P=0.010). MYD88 mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic performance of the IPI. This study demonstrates the clinical utility of defining MYD88-mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies.
Subject(s)
Epstein-Barr Virus Infections , Lymphoma, Large B-Cell, Diffuse , Myeloid Differentiation Factor 88/genetics , Epstein-Barr Virus Infections/genetics , Herpesvirus 4, Human , Humans , In Situ Hybridization, Fluorescence , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/genetics , Mutation , PrognosisABSTRACT
A patient in his late 30s presented with symptoms consistent with a nephrotic syndrome. Renal biopsy revealed membranous nephropathy. He also mentioned a spontaneous resolving 'rash' at his glans penis after unprotected intercourse. Therefore, he was tested for sexually transmitted diseases as a possible underlying cause of his nephrotic syndrome. Serology for syphilis was positive with high titres. After a single penicillin injection, there was fast and complete clinical recovery.
Subject(s)
Glomerulonephritis, Membranous/etiology , Nephrotic Syndrome/etiology , Syphilis/complications , Adult , Glomerulonephritis, Membranous/pathology , Humans , Kidney/pathology , Kidney/ultrastructure , Male , Penicillins/therapeutic use , Syphilis/drug therapy , Syphilis SerodiagnosisABSTRACT
BACKGROUND: Forkhead box (FOXP3) is considered to be a specific marker for regulatory T cells. The aim of this study was to correlate intragraft FOXP3 at mRNA and cellular levels during renal allograft rejection to response to therapy and late clinical outcome. METHODS: Immunostainings and quantitative reverse-transcriptase polymerase chain reaction for FOXP3, CD3, and transforming growth factor (TGF)-beta were performed and results were related to histopathologic and clinical outcome. RESULTS: A good correlation between immunohistochemical analysis and mRNA levels for both CD3 and FOXP3 was observed. Intragraft FOXP3 was significantly related to tubulitis and interstitial fibrosis. A strong correlation was found between FOXP3 and CD3 mRNA and between FOXP3 and TGF-beta mRNA. No correlation was found between FOXP3 and response to therapy. DISCUSSION: In conclusion, intragraft FOXP3 at both cellular and molecular levels parallels T-cell infiltration during acute rejection. FOXP3 does not predict response to antirejection therapy. FOXP3 correlates with renal fibrosis, TGF-beta, and poor late renal outcome.
