Annunziata Gloghini

Point mutations of the BCL‐6 gene in Burkitt's lymphoma

BCL‐6 codes for a transcription factor implicated in chromosomal translocations of diffuse large cell lymphomas. Recent evidence indicates that BCL‐6 may also be altered by mutations of its 5′ non‐coding regions. In this study we have investigated the distribution of BCL‐6 5′ mutations among 35 Burkitts lymphoma cases representative of the epidemiologic variants of the disease. Mutations were detected in 6/21 (28.6%) sporadic Burkitts lymphomas and 7/14 (50%) endemic Burkitts lymphomas. These data expand the spectrum of B‐cell non‐Hodgkins lymphomas associated with BCL‐6 5′ mutations and have implications for the pathogenesis, histogenesis and clinical monitoring of Burkitts lymphoma.

Human herpesvirus type-8 (HHV-8) in haematopoietic neoplasia.

Human herpesvirus type-8 (HHV-8) is a lymphotropic herpesvirus originally identified in Kaposis sarcoma. Among lymphoproliferative disorders, HHV-8 infection is restricted to body-cavity-based lymphoma (BCBL) and multicentric Castlemans disease (MCD). BCBL are B-cell lymphomas growing in liquid phase in the body cavities and most frequently associated with AIDS. BCBL express indeterminate phenotypes, in all cases are associated with HHV-8 infection, and frequently carry Epstein-Barr virus genomes in the absence of c-MYC rearrangements or other genetic lesions characteristic of B-cell lymphomas. The clinical outcome of BCBL is poor with a median survival of only few months. MCD is an atypical lymphoproliferative disorder which displays marked vascular hyperplasia and is commonly associated with Kaposis sarcoma. HHV-8 infection occurs in 100% of AIDS-related MCD and in approximately 40% of AIDS-unrelated cases. Overall, the consistency of HHV-8 infection in BCBL and MCD, its selectivity throughout the spectrum of lymphoproliferative disorders and the high copy number of HHV-8 DNA sequences in infected cells suggest that the virus plays a pathogenetic role in these disorders.

Association of Epstein-Barr Virus with Hodgkin’s Disease

The nature of Hodgkin’s disease (HD) and the origin of its characteristic cells, the Reed-Sternberg (RS) cells, are still obscure in spite of the abundant literature on this disorder. In recent years, the concept that HD is a malignant lymphoma has become widely accepted among pathologists, clinicians, and medical researchers working on this disease. However, the evidence accumulated so far with regard to the standard parameters defining neoplastic proliferation, such as clonality, chromosomal abnormality, and transplantability, is still controversial. A further enigma concerning HD as a neoplastic lymphoproliferative disease is the extremely low percentage of putative neoplastic cells (RS cells and their variants) occurring in the polymorphic histopathological setting that characterizes the disease. In contrast, well-recognized neoplastic lymphoproliferative diseases, the so-called non-Hodgkin’s lymphomas (NHLs), usually show monomorphic histological patterns and are constituted predominantly of monoclonal or, more rarely, oligoclonal cell populations.

Genetic Markers in Sporadic Tumors

Progress in understanding the molecular basis of neoplastic transformation has strengthened the concept that cancer is a genetic disease. This concept, however, lumps together two types of genetic diseases with the same outcome: the first linked to an entirely somatic cell-gene deregulation and the second dealing with a genetic susceptibility. At the somatic cell level, deregulation of cancer genes that control the careful balance between increase in cell number and withdrawal from the cell cycle promotes neoplastic growth by disrupting this balance. This deregulation occurs as a result of circumvention of the apoptotic machinery, promotion of cell division and cell proliferation, loss of cell differentiation pathways, and disruption of cell-cell communication and interaction. Thus, cancer represents the end point of a multistep process involving cancer genes and stimulatory and inhibitory signals provided by and controlled by products of the cancer genes.

Aids-Related Non-Hodgkin Lymphomas

AIDS-related non-Hodgkin lymphomas (AIDS-NHL) are almost invariably derived from B cells and are grouped into three distinct histologic categories, including small non cleaved cell lymphoma (SNCCL), diffuse large cell lymphoma (DLCL), and anaplastic large cell lymphoma (ALCL). In addition, AIDS-NHL presenting solely as a body cavity effusion are thought to be a peculiar clinico-pathologic entity and are defined as body-cavity-based lymphoma (BCBL). At the biologic level, AIDS-related lymphomagenesis is characterized by activation of proto-oncogenes, inactivation of tumor suppressor genes, viral infection of the tumor clone, and deregulated cytokine production. Distinct AIDS-NHL types associate with specific molecular pathways. The first pathogenetic pathway clusters with AIDS-SNCCL, and is characterized by a relatively mild degree of host immunodeficiency. AIDS-SNCCL consistently associates with c-MYC rearrangements and p53 inactivation in 100% and 60% of the cases respectively, whereas infection by Epstein-Barr virus (EBV) is restricted to 30% of the cases. Production of high levels of IL-10 is an additional peculiar feature of EBV positive AIDS-SNCCL. The second pathogenetic pathway associates with AIDS-DLCL, which is usually accompanied by a marked immunodeficiency of the host. AIDS-DLCL is characterized by EBV infection in the large majority of cases and by the mutually exclusive presence of BCL-6 rearrangements and c-MYC translocation in 40% of the cases. A third pathway characterizes AIDS-BCBL, which associates virtually in all cases with infection by EBV and with the presence of DNA sequence of the recently identified Kaposi sarcoma herpes virus (KSHV) in the apparent absence of other known genetic lesions. Finally, the pathogenetic features of AIDS-ALCL are still under investigation.