Gaidano, G.

Experimental Oncology

Наукова електронна бібліотека періодичних видань НАН України (Vernadsky National Library of Ukraine)

Experimental Oncology ��� �������� ���� ��ecem�er� ���CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood 2012; 119: 5126–32.32. Czuczman MS, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: re-sults from a multicenter study. Blood 2012; 119: 3698–704.VIRUSES AND LYMPHOMAG. GaidanoDivision of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, ItalyCorrespondence: gaidano@med.unipmn.itResearch on oncogenic infectious agents� espe-cially viruses� has helped us to understand the process of malignant transformation of cells �ecause the cel-lular events in viral-driven transformation mirror� often �rilliantly� �asic cellular processes that culminate in cancer� even those not associated with viruses. In-fectious agents� especially viruses� account for several of the most common malignancies — up to ��% of all cancers. Some of these cancers are endemic� with a high incidence in certain geographic locations� �ut sporadic/lower incidence in other parts of the world. Lymphomas arise frequently in association with viruses such as Epstein-Barr virus� human herpesvirus � �HHV-��� human immunodeficiency virus �HIV�� human T-lymphotropic virus-� �HTLV-��� and hepatitis C virus �HCV�. Viruses may contri�ute to lymphomagenesis either �y directly infecting the tumor clone �e.g. EBV� HHV�� HTLV-��� or via indirect mechanisms altering the host immunity �e.g. HIV� or microenvironmental interactions �e.g. HCV�.Gamma-herpesviruses. Two lymphotropic hu-man gamma herpesviruses can cause� or predispose to� lymphoproliferative disorders: Epstein — Barr virus �EBV� formally designated as human herpesvirus �� and Kaposi sarcoma herpesvirus �KSHV� also called human herpesvirus ��. Individuals with inherited or ac-quired immunodeficiency have a greatly increased risk of developing a malignancy caused �y one of these two viruses. Specific types of EBV- or HHV-� related lymphomas occur predominantly or almost exclusively in individuals with HIV infection� transplant recipients and children with primary immunodeficiency. Some of these diseases� such as Hodgkin and non-Hodgkin lymphoma resem�le those occurring in immunocom-petent patients� �ut the proportion of tumors in which EBV is present is increased. Others� like primary ef-fusion lymphoma and polymorphic post-transplant lymphoproliferative disorders� are rarely seen outside the context of a specific immunodeficient state.HIV. The clinical features and natural history of HIV-associated lymphomas differ greatly from those o�-served in the general population. The failure to improve outcomes with treatment intensification indicates the need for the introduction of new therapeutic options. HIV-associated lymphomas still represent a relevant field of clinical research. Standard methodologies for therapy in this patient population have yet to �e esta�-lished. However� rituxima� plus chemotherapy should �e offered to the majority of patients with HIV infection and diffuse large B-cell lymphoma and the feasi�ility of intensive aggressive chemotherapy regimens has �een successfully tested in HIV-associated Burkitt lymphomas.HTLV-I. Adult T-cell leukemia-lymphoma �ATLL� is a peripheral T-cell malignancy� closely associated with HTLV-� infection. Clinically� ATLL is classified into four su�types: acute� lymphoma� chronic and smol-dering type. Although the prognosis of chronic and smoldering-type ATLL is relatively good� that of pa-tients with acute- or lymphoma-type ATLL still remains extremely poor. Zidovudine/IFN-a therapy seems to �e promising� although its efficacy has not yet �een confirmed in well-designed prospective studies. High-dose chemotherapy with the support of autologous transplantation does not improve outcome. Allogeneic stem cell transplantation is promising and approxi-mately ��% of aggressive ATLL patients are expected to survive long-term� although transplantation-related mortality is as high as ���5�%.HCV. HCV is well known for its aetiological role in chronic non-A� non-B viral hepatitis� liver cirrhosis and hepatocellular carcinoma; in addition� the virus has also �een implicated in a num�er of extra-hepatic “autoimmune” disease manifestations. A causative association �etween HCV and non-Hodgkin lym-phoma �NHL� was postulated relatively recently and has �een the su�ject of intense investigation� as well as some de�ate. On the strength of epidemiological data� emerging �iological investigations and clini-cal o�servations� HCV appears to �e involved in the pathogenesis of at least a proportion of patients with NHL. Morphologically� HCV-associated lymphomas represent a variety of histological su�types including marginal zone lymphoma �splenic� nodal and extrano-dal�� small lymphocytic lymphoma/chronic lympho-cytic leukaemia� lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma. Remarka�ly� some HCV-associated NHL appear to �e highly responsive to antiviral therapy� providing some clinical evidence for this relationship� as well as the prospect for novel therapeutic intervention.Perspectives. Some virus-related lymphomas may �e difficult to treat with conventional approaches. �espite recent advancements using cytotoxic� lym-phoma-specific� and adoptive therapies� the long-term outcome of patients with y-herpesvirus lymphomas occurring in severely immunocompromised patients and ATLL continues to �e poor. Lytic-inducing thera-pies targeting NF-kB, and viral and tumor cell epigen-etic mechanisms afford the advantage of exploiting the intrinsic presence of oncogenic viruses to eradicate infected tumor cells. On these grounds� novel clinical approaches targeting viral latency are currently �eing investigated.REFERENCES1. Carbone A, Gaidano G. Acquired immunodeficiency syn-drome-related cancer. A study model for the mechanisms con-tributing to the genesis of cancer. Eur J Cancer 2001; 37: 1184–7.��� Experimental Oncology ��� �������� ���� ��ecem�er�2. Cesarman E. Gammaherpesvirus and lymphoprolifera-tive disorders in immunocompromised patients. Cancer Lett 2011; 305: 163–74.3. Gaidano G, Capello D, Carbone A. The molecular basis of acquired immunodeficiency syndrome-related lymphoma-genesis. Semin Oncol 2000; 27: 431–41.4. Gaidano G, Carbone A. Primary effusion lympho-ma: a liquid phase lymphoma of fluid-filled body cavities. Adv Cancer Res 2001; 80: 115–46.5. Gantt S, Casper C. Human herpesvirus 8-associated neoplasms: the roles of viral replication and antiviral treatment. Curr Opin Infect Dis 2011; 24: 295–30l.6. Marcucci F, Mele A. Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 2011; 17: 1792–8.7. Michieli M, Mazzucato M, Tirelli U, De Paoli P. Stem cell transplantation for lymphoma patients with HIV infection. Cell Transplant 2011; 20: 351–70.8. Ramos JC, Lossos IS. Newly emerging therapies target-ing viral-related lymphomas. Curr Oncol Rep 2011; 3: 4l6–26.9. Spina M, Gloghini A, Tirelli U, Carbone A. Therapeutic options for HIV-associated lymphomas. Expert Opin Pharma-cother. 2010; 11: 2471–81.10. Yodoi J, Maeda M. Discovery of ATL: an odyssey in restrospect. Int J Hematol 2011; 94: 423–8.LEUKEMIC PHASE OF B-LINEAGE NHLE. KimbyDepartment of Hematology, Karolinska Institute at Huddinge University Hospital Stockholm S-141 86, SwedenCorrespondence: eva.kimby@swipnet.seB-cell non-Hodgkin lymphomas �NHL� mostly pres-ent as disseminated diseases involving lymph nodes� spleen and liver and often the �one marrow �BM�. Tumor cells can also �e found in the �lood �leukemic disease�� especially in the indolent lymphomas. High white �lood cell counts and a differential demonstra-ting a lymphocytosis in the �lood require immunophe-notyping for characterization of the leukemic cells. Molecular/cytogenetic analyses may also have a role in the diagnostic classification of the disease. Besides the specific diagnosis� the clinical evaluation of the pa-tient and prognostic markers are of most importance for selecting the �est type of therapy.Follicular lymphoma (FL) is the indolent lymphoma with the highest incidence. Most patients present with advanced stage disease with BM involvement in �����% of the cases� and few are leukemic at the time of diagnosis. By high-resolution analysis circulating FL cells may �e detected in more patients. Leukemic pa-tients mostly have concomitant lymph node involvement and high tumor �urden. A pure FL-cell leukemia with C���+C���+C�5� clonal cells has also �een descri�ed� mostly associated with an indolent clinical outcome. FL carry a t�l�;l���q��;q�l� translocation in more than 9�% of cases� juxtaposing the immunoglo�ulin heavy chain �IGH� �’ Regulatory Regions �lgH-�’RR� to the BCL2 gene� resulting in overexpression of the Bcl� anti-apoptotic protein. FL cells are also dependent on signals from the microenvironment to survive and proliferate. Several groups� including ours� have reported that immune cells in the lymphoma microenvironment and in �lood influence prognosis. In patients treated �efore the introduction of rituxima�� we have found that a high num�er of P�-�+� FOXP�+ and C��+ T-cell su�sets in the tumor microenvironment predict superior outcome� while C��+ follicular helper T cells and C�6�+ macro-phages are associated with an inferior outcome. The introduction of the anti-C��� anti�ody rituxima� has improved the prognosis for FL patients. The efficacy of this drug is excellent also as monotherapy especially in patients with high num�ers of C��+ T-cells in the lymph nodes as well as in the �lood.Mantle cell lymphoma (MCL): MCL cells carries the t�l �:��� translocation resulting in enhanced cyclin �l expression and cyclin �I-dependent kinase activ-ity� promoting cell cycle progression. Immunological markers show a typical phenotype �C���+C�5+C������ �ut also atypical phenotypes �C���+C�5�C���� or C���+C�5+C���+� in some cases. Most MCL patients have an unfavora�le prognosis and intensive treatment strategies are required. However� in around ��% of the patients the disease shows an indolent clinical course with often a non-nodal� leukemic disease. In one study the clinicopathologic features� gene expression and genomic profiles were compared in patients with in-dolent �iMCL� and in those with conventional disease �cMCL�. iMCL and cMCL shared a common gene expression profile that differed from other leukemic lymphoid neoplasms and a signature of �� genes was underexpressed in iMCL� among these SOXI1. The SOX I1-negative tumors exhi�ited more frequent non-nodal presentation and �etter survival compared with SOX I1-positive MCL. Recently� our group found that SOXII-negative MCL had a higher frequency of lymphocytosis� �ut also elevated L�H and p5� positivity. Moreover� SOXII- negative cases had a shorter overall survival than SOXII-positive cases. �ue to the conflicting results� the conclusion is that SOXII cannot �e used for predicting an indolent disease course. In another study� deletions at ��p�� (TP53) and ��q�� were frequent in leukemic MCL and involved the majority of the leukemic clone. Cases with TP53 deletion were more likely to have splenomegaly and marked leucocytosis �> �� × ��9/L�� and were less likely to have lymphadenopathy than those without the deletion. Other distinctive �iological features in non-nodal leukemic MCL are mutated IGHV and a transcriptional profile lacking tumor invasion prop-erties� which might contri�ute to the a�sence of nodal involvement. In conclusion� MCL patients with leukemic disease �ut without clinical symptoms might �e man-aged conservatively with a “wait and watch” policy� while �lastoid morphology� high proliferation and TP53 a�er-rations are markers of aggressive disease� which will require intensive immunochemotherapy.Marginal zone lymphoma (MZL): There are three clinicopathological entities of MZL� including extranod-al� mucosa-associated lymphoid tissue �MALT� lympho-ma� nodal �NMZL�� and splenic �SMZL� type. Leukemic presentation is more common in SMZL. The leukemic 

Viruses and lymphoma

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Viruses and lymphoma

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Наукова електронна бібліотека періодичних видань НАН України (Vernadsky National Library of Ukraine)