Aberrant somatic hypermutation in primary mediastinal large B-cell lymphoma.
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Adult↗
Biomedical subjects
G Gaidano
Publications and source records attributed to G Gaidano.
KSHV/HHV-8 associated lymph node based lymphomas in HIV seronegative subjects. Report of two cases with anaplastic large cell morphology and plasmablastic immunophenotype.
BACKGROUND: Kaposi sarcoma associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) associated lymphomas, which often develop in human immunodeficiency virus (HIV) infected patients with advanced AIDS, present predominantly as primary effusion lymphoma (PEL) or, less frequently, as "solid" extracavitary based lymphomas, associated with serous effusions. These last lymphomas, also called "solid PEL", have been reported before the development of an effusion lymphoma and after resolution of PEL. Interestingly, KSHV/HHV-8 associated lymphomas that present as solid or extracavitary based lesions in HIV seropositive patients without serous effusions have been reported recently. METHODS/RESULTS: This paper provides evidence for the existence of a previously undescribed KSHV/HHV-8 associated lymphoma in HIV seronegative patients without serous effusions. These lymphomas exhibit a predilection for the lymph nodes and display anaplastic large cell morphology. These tumours were completely devoid of common cell type specific antigens, including epithelial and melanocytic cell markers. B and T cell associated antigens and other commonly used lymphoid markers were absent or weakly demonstrable in a fraction of the tumour cells. Conversely, immunohistochemical studies showed strong immunostaining with plasma cell reactive antibodies. CONCLUSIONS: Analysis of viral infection and immunohistological studies are of primary importance to define this lymph node based KSHV/HHV-8 associated lymphoma with anaplastic large cell morphology and plasmablastic immunophenotype occurring in HIV seronegative patients without serous effusions.
Aged↗
Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia.
Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (VH) and light (VL) chain gene usage in highly stable and indolent B-CLL (n=25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated VH3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; P<0.01), including mutated cases (6/432; 1.39%; P<0.01) and was exceptional among indolent (1/230, 0.435%; P<0.01), and aggressive B-cell lymphomas (0/105; P<0.01). Three of six VH3-72 B-CLL cases utilized the same VL Vkappa4-1 gene. Two V(H)3-72 B-CLL cases had highly homologous VH complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized Vkappa4-1 genes with homologous IgVL CDR3s. An identical threonine to isoleucine change at codon 84 of V(H)3-72 framework region 3 (FR3) recurred in four cases of highly stable VH3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by VH3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.
Amino Acid Sequence↗
Post-transplant lymphoproliferative disorders. Molecular analysis of histogenesis and pathogenesis.
AIM: Post-transplant lymphoproliferative disorders (PTLD) represent a serious complication of solid organ transplantation. Despite several advances in the biological categorization of PTLD, current classifications are not fully predictive of the clinical behavior of the disease. This study assessed a comprehensive molecular analysis of the clinico-pathologic spectrum of PTLD in order to better clarify the physiopathology of these disorders. METHODS: Fifty-two monoclonal PTLD were investigated for: 1). somatic hypermutation of IgV genes by direct sequencing of IgV rearrangements; 2). expression of BCL6, MUM1 and CD138 proteins by immunohistochemistry; 3). aberrant hypermethylation of DAP-kinase gene by methylation-specific polymerase chain reaction (PCR); 4). genotypic characterization of Epstein Barr virus (EBV) in EBV infected PTLD by PCR analysis of the prevalence of deletions in the carboxyterminal portion of the LMP1 gene and for the definition of type-1/type-2 EBV infection. RESULTS: We report that virtually all monoclonal PTLD originate from B cells that have experienced the germinal center (GC) reaction reflecting different stages of mature B cell differentiation and that tumor development seems frequently associated with EBV and/or other molecular lesions preventing apoptosis of cells that have failed the physiological process of germinal center reaction. CONCLUSION: To date, classification of PTLD is mainly based on morphology and conventional immunophenotyping. Because current classification schemes are not fully predictive of prognosis, knowledge of PTLD histogenesis and pathogenesis may potentially contribute to refine the distinction of PTLD into more homogeneous categories with prognostic relevance.
Adolescent↗
Post gravidic superior sagittal sinus thrombosis with elevated levels of homocystinemia.
Cerebral ischemia in the young (less than 45 years) is an uncommon finding, its ethiology remaining undefined in up to half of cases even if all the common diagnostic paths have been followed. Pregnancy and puerperium are characterised by an increased risk of ischemic stroke and intracranial venous thrombosis. We present a case of a young woman with post gravidic thrombosis of the superior sagittal sinus, occurred 10 days after eutocic delivery. She presented elevated plasma levels of homocystinemia, a sulphur containing amino acid that induce complex changes within the blood vessel wall, acting with an oxidative stress and with a reduction of nitric oxide availability. This clinical case suggests that a complete screening for thrombophilic risk factors should be an integral part in the diagnostic path of central venous thrombosis in young patients also in the puerperium, because it allows to identify thrombophilic risk factors requiring specific treatment.
Adult↗
Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma.
Although point mutations of the 5' noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.
Adolescent↗
Primary follicular lymphoma of the testis in childhood: an entity with peculiar clinical and molecular characteristics.
BACKGROUND/AIMS: Paediatric primary follicular lymphoma of the testis (PPFLT) is exceptional: the few reported cases seem to lack BCL-2 gene rearrangement and/or protein expression. The aim of this study was to characterise a PPFLT arising in a 4 year old boy. METHODS: This case was characterised using conventional histological analysis, immunohistochemistry, and a polymerase chain reaction based method for the detection of immunoglobulin V(H) chain rearrangements. RESULTS: The neoplasm was staged I(E)/A; left orchiectomy and chemotherapy were performed, producing complete remission. Histology showed a predominantly follicular lymphoid infiltrate mainly composed of centroblast-like cells. The phenotype was CD20(+), CD79a(+), CD10(+), bcl-6(+), B cell specific activating protein(+), kappa light chain(+), CD30(-/+), interferon regulating factor 4(-/+), c-myc(-/+), lambda light chain(-), CD3(-), bcl-2(-), p53(-), cytokeratin(-), and placental alkaline phosphatase(-). Lymphomatous elements were found within a CD21(+) follicular dendritic cell network and 70% were positive for Ki-67/MIB-1. Molecular analysis revealed monoclonal immunoglobulin heavy chain gene rearrangement and BCL-6 mutations, in the absence of BCL-2 major breakpoint and BCL-2 minor cluster region rearrangements, p53 mutations, and death associated protein kinase gene hypermethylation. CONCLUSIONS: These findings suggest a different pathogenesis of PPTFL compared with adult follicular lymphoma and might explain its favourable course in spite of aggressive histology.
Child, Preschool↗
Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia.
Deletions of the 13q14 chromosome region are associated with B-cell chronic lymphocytic leukemia (B-CLL) and several other types of cancer, suggesting the presence of a tumor suppressor gene. In previous studies the minimal region of deletion (MDR) was mapped to a less than 300-kilobase (kb) interval bordered by the markers 173a12-82 and 138G4/1.3R. For the identification of the putative tumor suppressor gene, the entire MDR (approximately 347 kb) has been sequenced, and transcribed regions have been identified by exon trapping, EST-based full-length complementary DNA cloning, database homology searches, and computer-assisted gene prediction analyses. The MDR contains 2 pseudogenes and 3 transcribed genes: CAR, encoding a putative RING-finger containing protein; 1B4/Leu2, generating noncoding transcripts; and EST70/Leu1, probably representing another noncoding gene (longest open reading frame of 78 codons). These genes have been sequenced in 20 B-CLL cases with 13q14 hemizygous deletion, and no mutations were found. Moreover, no somatic variants were found in the entire MDR analyzed for nucleotide substitutions by a combination of direct sequencing and fluorescence-assisted mismatch analysis in 5 B-CLL cases displaying 13q14-monoallelic deletion. The nondeleted allele of the CAR and EST70/Leu1 genes was expressed in B-CLL specimens, including those with monoallelic loss, whereas no expression of 1B4/Leu2 was detectable in B-CLL, regardless of the 13q14 status. These results indicate that allelic loss and mutation of a gene within the MDR is an unlikely pathogenetic mechanism for B-CLL. However, haplo-insufficiency of one of the identified genes may contribute to tumorigenesis. (Blood. 2001;97:2098-2104)
Animals↗
Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas.
This study was aimed at defining the histogenesis of the pathologic spectrum of lymphoma arising in the context of human immunodeficiency virus (HIV) infection. Toward this aim, 87 AIDS-related non-Hodgkin lymphomas (AIDS-NHL) and 16 Hodgkin lymphomas arising in HIV+ patients (HIV-HL) were comparatively analyzed for the expression pattern of several B-cell histogenetic markers, including BCL-6 (expressed by centroblasts and centrocytes), MUM1/IRF4 (expressed by late centrocytes and post-germinal center [GC] B cells), and CD138/syn-1 (expressed by post-GC B cells). Expression of MUM1, BCL-6, and syn-1 segregated 3 major phenotypic patterns among AIDS-NHL and HIV-HL: (1) the BCL-6+/MUM1-/syn-1- pattern, selectively clustering with a large fraction of AIDS-Burkitt lymphoma (17 of 19) and of systemic AIDS-diffuse large cell lymphoma (12 of 16); (2) the BCL-6-/MUM1+/syn-1- pattern, associated with a fraction of AIDS-immunoblastic lymphoma (8 of 24); and (3) the BCL-6-/MUM1+/syn-1+ pattern, associated with systemic and primary central nervous system immunoblastic lymphoma (14 of 24) and with primary effusion lymphoma (10 of 10), plasmablastic lymphoma of the oral cavity (7 of 7), and HIV-HL (15 of 16). Analysis of nonneoplastic lymph nodes showed that the 3 phenotypic patterns detected in AIDS-NHL and HIV-HL correspond to distinct stages of physiologic B-cell development-centroblasts (BCL-6+/MUM1-/syn-1-), late GC/early post-GC B cells (BCL-6-/MUM1+/syn-1-), and post-GC B cells (BCL-6-/MUM1+/syn-1+). Expression of the Epstein-Barr virus-encoded latent membrane protein-1 clustered with the BCL-6-/MUM1+/syn-1+ profile throughout the clinicopathologic spectrum of AIDS-NHL and HIV-HL. Overall, these results define novel histogenetic subsets of AIDS-NHL and HIV-HL and may provide novel tools for refining the diagnosis of these disorders.
B-Lymphocytes↗
Primary effusion lymphoma in HIV-infected patients with multicentric Castleman's disease.
Multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) are two B-cell lymphoproliferative diseases associated with Kaposi's sarcoma-associated herpes virus/human herpesvirus-8 (KSHV/HHV-8). Although MCD is considered a prelymphoma state, it is not known whether a pathogenetic link exists between MCD and PEL. This paper reports the clinico-pathological features of four cases of PEL (two pericardial, one pleural, and one peritoneal) developing in the context of HIV-associated MCD. Effusions, lymph nodes, spleen, and additional tissues from three autopsies were examined for morphology/immunophenotype, search for HHV-8 DNA, and assessment of immunoglobulin heavy chain gene (IgH) configuration using polymerase chain reaction (PCR)-based techniques. MCD and PEL samples contained HHV-8 DNA. Clonal IgH rearrangements were detected only in PEL, whereas MCD tissues were polyclonal. Light-chain immunostaining confirmed B-cell clonality in PEL (two lambda, one kappa, one not tested) and polyclonality in MCD. The autopsies revealed different morphological variants of visceral KS and multi-organ atypical infiltrates exhibiting immunoblastic/plasmablastic features reminiscent of PEL morphology, with a restriction of lambda-positive cells. In two cases, using microdissection and IgH PCR analysis, multiple/discrete bands were found in the infiltrates, compatible with polyclonality/oligoclonality. The case showing an oligoclonal IgH ladder contained a rearrangement of identical junctional size to the PEL clone; however, further analysis with PEL-derived clonotypic primers and sequencing of PCR products showed no amplification and nucleotide diversity, respectively, indicating that the two B-cell populations examined were clonally unrelated. These data show that MCD and PEL may co-exist in HIV-infected patients, suggesting a relevant association between these two HHV-8-related disorders. Although a definite clonal relationship between MCD and PEL was not demonstrated, it is hypothesized that in some MCD cases, within expanded polyclonal B-cell populations secondary to HHV-8 infection, clonal expansions may occur that localize into a body cavity, i.e. PEL.
Adult↗
Primary effusion lymphoma: a liquid phase lymphoma of fluid-filled body cavities.
Primary effusion lymphoma (PEL) is a B-cell neoplasm characterized by infection of the tumor clone by human herpesvirus type-8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV) and by liquid growth in fluid-filled body spaces. During its entire clinical course, the lymphoma tends to remain localized to the serous body cavities with no formation of solid tumor masses. The epidemiology of PEL points to a close link with underlying immunodeficiency of the host, as most cases develop in individuals severely immunocompromised because of preexisting acquired immunodeficiency syndrome. The histogenesis and pathogenesis of PEL have been clarified to a sizeable extent by intensive investigations performed since the disease recognition in 1995. PEL is composed of postgerminal center B cells, which bridge immunoblastic and anaplastic features and typically display a non-B, non-T phenotype consistent with late stages of B-cell differentiation. HHV-8/KSHV is thought to play a major role in PEL pathogenesis via expression of several viral latent genes, which have the potential to affect B-cell growth. Other factors involved in PEL pathogenesis include deregulation of cytokine and growth factor autocrine loops, molecular alterations of the tumor DNA, cell cycle abnormalities, stimulation and selection by antigen, and infection by Epstein-Barr virus, which occurs in 70% of PEL cases. In the years since the disease discovery, the distinctiveness of the biological and clinicopathological features of PEL has prompted its recognition as an independent lymphoma category by the World Health Organization classification system of hematologic neoplasms.
Diagnosis, Differential↗
Acquired immunodeficiency syndrome-related cancer. A study model for the mechanisms contributing to the genesis of cancer.
The study of AIDS and cancer has resulted in an important convergence of clinical-epidemiological investigations, molecular research and virological studies. This shared effort has led to significant discoveries in the field of human carcinogenesis. In a relatively short time, several topics have been clarified, namely: (1) the spectrum of AIDS-related tumours has been identified; (2) the role of HIV in lymphomagenesis and in the development of Kaposi's sarcoma (KS) has been defined; (3) AIDS-related cancers have allowed the discovery and extensive biological characterisation of the novel virus human herpes virus 8 (HHV8), also called KS-associated herpesvirus; and (4) genetic, molecular, and phenotypic studies of AIDS-related lymphomas have contributed to the formulation of a pathogenetic and histogenetic model of B-cell non-Hodgkin's lymphomas (NHL).
Acquired Immunodeficiency Syndrome↗
Genetic pathways and histogenetic models of AIDS-related lymphomas.
Acquired immunodeficiency syndrome (AIDS)-related lymphomas consistently display a B-cell phenotype and are histogenetically related to germinal centre or post-germinal centre B cells in the overwhelming majority of cases. The pathogenesis of AIDS-related lymphoma is a multistep process involving factors provided by the host as well as alterations intrinsic to the tumour clone. The molecular pathways of viral infection and lesions of cancer-related genes associated with AIDS-related lymphomas vary substantially in different clinicopathological categories of the disease and highlight the marked degree of biological heterogeneity of these lymphomas.
Burkitt Lymphoma↗
Severe thrombocytopenia and clinical bleeding associated with rituximab infusion in a lymphoma patient with massive splenomegaly without leukemic invasion.
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Antibodies, Monoclonal↗
Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin's lymphomas.
PURPOSE: This study aimed at correlating Epstein-Barr virus (EBV) infection of systemic AIDS-related non-Hodgkin lymphomas (AIDS-NHL) with the development of a CNS localization of the tumor. PATIENTS AND METHODS: Demographic, epidemiologic, clinical, histologic, and virologic features were collected for all systemic AIDS-NHL patients included in the study (n = 50). Pathologic specimens were classified according to the working formulation for NHL and the Revised European-American Lymphoma classification. EBV infection in tumor tissue samples was studied by EBV small encoded RNA in situ hybridization; EBV-DNA detection in CSF was carried out by nested polymerase chain reaction using Epstein-Barr nuclear antigen-1-specific primers. In addition, selected EBV-positive lymphomas were subjected to a detailed characterization of EBV molecular heterogeneity. RESULTS: Eleven patients had a CNS involvement at some point during their clinical history (four at diagnosis and seven at relapse). Thirty patients (11 with CNS involvement and 19 without) harbored EBV infection of the tumor. Sensitivity, specificity, and positive and negative predictive values of EBV-DNA detection in CSF for CNS involvement by lymphoma were 90%, 100%, 100%, and 97.6%, respectively. Factors significantly predictive of CNS involvement were EBV infection of the tumor (P=.003), an extranodal disease at diagnosis other than CNS (P=.006), and a non-CNS relapse (P=.01). In four cases of CNS involvement, EBV-DNA in CSF preceded any other sign of disease by a mean of 35 days. CONCLUSION: These results show that EBV infection of the tumor clone significantly increases the risk of CNS involvement by systemic AIDS-NHL, without regard of specific molecular features. The detection of EBV-DNA in the CSF of AIDS-NHL patients may select cases with higher risk of CNS involvement and, therefore, may prove useful in the therapeutic stratification of these tumors.
Adult↗
An apparent interlocus gene conversion-like event at a putative tumor suppressor gene locus on human chromosome 6q27 in a Burkitt's lymphoma cell line.
A region of minimal deletion in B-cell non-Hodgkin's lymphoma (B-NHL) has recently been defined between D6S186 and D6S227 spanning 5-9 Mb at 6q26-q27, predicting the presence of at least one tumor suppressor gene (TSG) at this locus. During the construction of a deletion map in the B-NHL tumor panel, we report the identification of a Burkitt's lymphoma cell line, BL74, having an apparent homozygous deletion at the D6S347 locus, internal to the critical region. Since this case may facilitate the localization of the target TSG, a detailed structural molecular characterization and search for candidate genes were undertaken at this locus. While BL74 underwent a loss of heterozygosity at 6q26-q27, D6S347 was also likely subjected to a somatic interlocus gene conversion-like event between two homologous but distinct loci, resulting in the homozygous replacement of a 1860- to 2067-bp segment of one locus with the corresponding segment copied from the other locus. Two genes at this locus were identified, but their lack of expression in B-cell lineages tentatively excludes them as candidate TSGs. Another still unidentified gene at this locus may be disrupted by the gene conversion-like event, which would represent a novel mechanism of TSG inactivation.
Alleles↗
Epidemiological, biological and clinical features of HIV-related lymphomas in the era of highly active antiretroviral therapy.
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Anti-HIV Agents↗
Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia.
BCL-6 mutations are accumulated during B-cell transit through the germinal center (GC) and provide a histogenetic marker for B-cell tumors. On the basis of a comprehensive analysis of 308 B-cell neoplasms, we (1) expand the spectrum of tumors associated with BCL-6 mutations; (2) corroborate the notion that mutations cluster with GC and post-GC B-cell neoplasms; and (3) identify heterogeneous mutation frequency among B-lineage diffuse large cell lymphoma (B-DLCL) subsets. Mutations are virtually absent in acute lymphoblastic leukemia (P <.001) and mantle cell lymphoma (P <.05), whereas they occur frequently in GC or post-GC neoplasms, including lymphoplasmacytoid lymphoma, follicular lymphoma, MALT lymphomas, B-DLCL and Burkitt lymphoma. Among B-DLCL, mutations occur frequently in systemic nodal B-DLCL, primary extranodal B-DLCL, CD5(+) B-DLCL, CD30(+) B-DLCL, and primary splenic B-DLCL, suggesting a similar histogenesis of these B-DLCL subsets. Conversely, mutations are rare in primary mediastinal B-DLCL with sclerosis (10.0%; P <.01), supporting a distinct histogenesis for this lymphoma. Longitudinal follow-up of B-DLCL transformed from follicular lymphoma shows that they BCL-6 mutations may accumulate during histologic progression. Mutations also occur in some B-cell chronic lymphocytic leukemias, small lymphocytic lymphomas, and hairy cell leukemias, consistent with the hypothesis that a fraction of these lymphoproliferations are related to GC-like cells. Finally, the molecular pattern of 193 mutational events reinforces the hypothesis that mutations of BCL-6 and immunoglobulin genes are caused by similar mechanisms. (Blood. 2000;95:651-659)
Base Sequence↗