Indolent B-cell lymphomas associated with HCV infection: clinical and virological features and role of antiviral therapy.

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 638185, 10 pages doi:10.1155/2012/638185 Review Article Indolent B-Cell Lymphomas Associated with HCV Infection: Clinical and Virological Features and Role of Antiviral Therapy Luca Arcaini,1 Michele Merli,2 Stefano Volpetti,3 Sara Rattotti,1 Manuel Gotti,1 and Francesco Zaja3, 4 1 Department of Hematology Oncology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy 2 Division of Hematology, Department of Internal Medicine, Ospedale di Circolo, Fondazione Macchi, 21100 Varese, Italy 3 Department of Hematology, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, 33100 Udine, Italy 4 Clinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi”, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, p.le S. Maria Misericordia 15, 33100 Udine, Italy Correspondence should be addressed to Francesco Zaja, Received 16 May 2012; Revised 4 July 2012; Accepted 4 July 2012 Academic Editor: Jürg Schifferli Copyright © 2012 Luca Arcaini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin’s lymphomas (NHL) has been demonstrated by epidemiological studies, in particular in highly endemic geographical areas such as Italy, Japan, and southern parts of United States. In these countries, together with diffuse large B-cell lymphomas, marginal zone lymphomas are the histotypes most frequently associated with HCV infection; in Italy around 20–30% cases of marginal zone lymphomas are HCV positive. Recently, antiviral treatment with interferon with or without ribavirin has been proved to be effective in the treatment of HCV-positive patients affected by indolent lymphoma, prevalently of marginal zone origin. An increasing number of experiences confirmed the validity of this approach in marginal zone lymphomas and in other indolent NHL subtypes like lymphoplasmacytic lymphoma. Across different studies, overall response rate was approximately 75%. Hematological responses resulted significantly associated with the eradication of the virus. This is the strongest evidence of a causative link between HCV and lymphomas. The aim of this paper is to illustrate the relationship between HCV infection and different subtypes of indolent B-cell lymphomas and to systematically summarize the data from the therapeutic studies that reported the use of antiviral treatment as hematological therapy in patients with HCV-associated indolent lymphomas. 1. Introduction In the last two decades, evidences from either epidemiological studies, biological insights, and also therapeutic approaches provided strong support to the association between hepatitis C virus (HCV) and B-cell non-Hodgkin’s lymphomas (NHL). HCV has been associated with B-cell indolent lymphomas, especially marginal zone lymphomas, as well as with aggressive lymphomas, mainly diffuse large B-cell lymphomas. Indolent lymphomas are defined from a clinical point of view as scarcely symptomatic lymphomas, growing and spreading slowly [1] and encompass the following histologic subtypes of low-grade lymphoma according to the WHO classification [2]: follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphomas, splenic marginal zone lymphoma, primary nodal marginal zone lymphoma and extranodal marginal zone lymphoma of mucosa-associated tissue (MALT), and lymphoplasmacytic lymphoma. According to the currently more accepted pathogenetic model, the role of HCV infection in lymphomagenesis may be related to the chronic antigenic stimulation of B-cell immunologic response by the virus [3], similarly to the well-characterized induction of gastric MALT lymphoma development by Helicobacter pylori chronic infection [4]. In a similar way, chronic HCV infection may possibly sustain a multistep evolution from type II mixed cryoglobulinemia to overt low-grade NHL and eventually to high-grade NHL [3, 4]. The most convincing argument in favour of a causative link between HCV and lymphoproliferation is represented by interventional studies demonstrating that in HCV-positive patients affected by indolent NHL eradication of HCV with antiviral treatment (AT) could directly induce lymphoma 2 regression [5]. Moreover, the upcoming novel antiviral antiHCV agents as boceprevir and telaprevir, whose addition to standard treatment has already demonstrated an increased rate of viral eradication also in more resistant genotypes (i.e., genotype 1b) [6, 7], will possibly further improve the efficacy of this treatment for HCV-positive indolent NHL in the near future. 2. Methods The aim of this paper is to systematically summarize the available data indolent B-cell NHL associated with HCV infection and the up-to-now reported experiences with the use of AT with interferon with or without ribavirin as hematologic treatment in patients with HCV-positive indolent Bcell NHL. To this aim, we performed a systematic PubMed search (http://www.pubmed.gov/) using the keywords “indolent lymphoma,” “marginal zone lymphoma,” “MALT lymphoma,” “lymphoplasmacytic lymphoma,” “hepatitis C virus,” “interferon,” “ribavirin,” “antiviral therapy.” All relevant articles were included, as well as the most significant abstracts presented at American Society of Hematology (ASH) meetings and International Conference on Malignant Lymphomas (ICML) meetings since 2005. The articles were reviewed with reference to the features of HCV-associated indolent NHL and were assessed specifically concerning virological and hematological response in cases treated with AT. 3. HCV Infection, Cryoglobulinemia, and Lymphomas 3.1. HCV and Cryoglobulinemia. The initial finding that lead to the extensive investigation of the association between HCV and NHL was the very high prevalence (nearly 90–100%) of HCV infection in patients with type II mixed cryoglobulinemia [8]. Cryoglobulins are serum immunoglobulins that become insoluble and precipitate at temperatures below 37◦ C. The antigenic component of the immune complexes has been found to be highly enriched in viral HCV core protein and HCV-RNA. Type II mixed cryoglobulinemia is characterized by a mixture of monoclonal and polyclonal immunoglobulins. The monoclonal component of type II mixed cryoglobulinemia is an IgM/k with a rheumatoid-factor activity (i.e., anti-IgG cross-reactive binding) that reflects the expansion of a B-cell monoclonal population [9]. Overall, up to 50% of HCV-infected patients exhibit low levels of circulating mixed cryoglobulins, whereas overt cryoglobulinemic vasculitis develops in ≤5% of infected patients [10]. Symptoms vary from purpura and arthralgia to more severe manifestations like peripheral neuropathy and glomerulonephritis. Importantly, in HCV-infec (...truncated)