Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity
http://www.100md.com
《血液学杂志》
the Department of Hematology, hospital Necker, Paris, France
Department of Rheumatology, hospital de Kremlin-Bicêtre, Le Kremlin-Bicêtre, France
Department of Hematology, CHU Cte de Nacre, Caen, France
Department of Internal Medicine, hospital Pitie-Salpetrière, Paris, France.
Abstract
Hepatitis C virus (HCV) has been associated with the development of B-cell non-Hodgkin lymphomas. We recently reported the regression of splenic lymphoma with villous lymphocytes (SLVL) in patients with HCV after antiviral treatment, demonstrating a direct role of HCV in lymphomagenesis. This study expands our previous results in 18 patients with chronic HCV and SLVL. Mixed cryoglobulinemia (MC) was present in all cases and was symptomatic in 13 (72%). All patients were treated with interferon alone or in association with ribavirin. Hematologic and virologic responses were correlated. Fourteen (78%) patients achieved a sustained complete hematologic response after clearance of HCV RNA. Two patients had a virologic partial response and achieved a complete hematologic response. Two virologic nonresponders achieved partial hematologic response. Regardless of the response, monoclonal immunoglobulin gene rearrangement persisted after treatment. This study underscores the role of HCV in the lymphomagenesis and the benefit of antiviral treatment for patients presenting with HCV-driven lymphoproliferations.
Introduction
Hepatitis C virus (HCV) is associated with a spectrum of extrahepatic manifestations, mainly mixed cryoglobulinemia (MC). MC-producing B cells are mostly monoclonal and a significant proportion of MCs can evolve into overt B-cell lymphoma. As such, HCV-MC is considered as a low-grade B-cell lymphoproliferative disorder. A link between HCV infection and B-cell non-Hodgkin lymphoma (NHL) has been suggested by many epidemiologic studies.1-3 In a meta-analysis, the prevalence of HCV infection in patients with B-cell NHL was 15% compared to 1.5% in the general population.4 Although most histologic subtypes of B-cell lymphomas have been described in association with HCV,5 lymphoplasmacytic lymphomas, marginal zone lymphomas (MZLs), and large B-cell lymphomas are more common in individuals infected with HCV.3,6,7 These epidemiologic studies establish the association between HCV infection and B-cell NHL but shed no light on the pathogenic role of the virus in the development of lymphomas.
Splenic lymphoma with villous lymphocytes (SLVL) is a chronic B-cell lymphoproliferative disorder characterized by a clonal expansion of atypical B lymphocytes with villous projections in peripheral blood. SLVL involves mainly the spleen and the bone marrow. Villous lymphocytes have immunologic and Immunophenotypical characters of marginal zone lymphocytes. SLVL is usually treated by splenectomy or chemotherapy or both, with an overall 5-year survival rate of 80%.8
We recently reported the regression of SLVL in patients with HCV after antiviral treatment,9 demonstrating a direct role of HCV in lymphomagenesis. The present study expands our previous results in a cohort of 18 patients with chronic HCV and SLVL.
Study design
Between 1993 and 2003, investigators from several French centers reported data on 18 patients with SLVL and HCV infection who were treated with antiviral therapy. Clinical and biologic data and outcome were analyzed. The diagnosis of SLVL was based on the presence of typical clinical, hematologic, and immunologic findings as previously described.8,10 All blood smears and immunophenotype findings were reviewed by 2 expert cytologists (F.V. and X.T.). Patients positive for MC were defined as having MC in their serum more than 0.05 g/L on at least 2 determinations. Symptomatic MC was defined by serum MC associated with the triad of purpura-arthralgia-asthenia and sometimes with renal or neurologic involvement.11
Patients received 3 million IU recombinant interferon-2b (IFN -2b), subcutaneously, 3 times a week for 6 months. In case of a partial response (> 50%), treatment was continued until a complete clinical response was achieved. In SLVL/HCV+ patients, diagnosed after 1996, ribavirin (1000-1200 mg/d) was added to IFN treatment.
Complete response was defined as disappearance of HCV RNA, the resolution of splenomegaly, a platelet count more than 100 x 109/L, an absolute neutrophil count more than 1 x 109/L, a hemoglobin level more than 10 g/dL, and the absence of circulating blood villous lymphocytes. Partial response was defined by a palpable but reduced spleen size by at least 50%, associated with an improvement of the blood hematologic parameters over baseline (> 50%) and detectable HCV RNA. Treatment failure and disease progression were defined as a persistent or progressive increase in the number of peripheral blood villous lymphocytes or splenomegaly, respectively. Relapse was defined as a progressive increase in the number of peripheral blood villous lymphocytes or increasing splenomegaly after an initial complete or partial response.
Results and discussion
All 18 patients had type II MC with symptoms of MC vasculitis in 13 (72%; Table 1), a much higher frequency than usually noted in cryoglobulin-positive HCV patients.12 Clinical symptoms of MC preceded the diagnosis of SLVL in 7 patients (mean of 3.5 years before SLVL diagnosis) and were contemporaneous in the other 6 patients. Except for the usual absence of clinical or biologic MC, and the lack of response to antiviral treatment, HCV– SLVL is similar to HCV-associated SLVL.8,9,13 The strong association of type II MC and HCV-associated SLVL is an important finding of this study. SLVL may be integrated in the spectrum of cryoglobulin associated B-cell proliferations.
HCV genotype 1 was observed in 7 of our patients. Despite of the usual resistance of this genotype to antiviral therapy, 4 of these patients achieved a complete hematologic response after INF and ribavirin.
Four patients had received a first-line therapy for SLVL (splenectomy, n = 2; chemotherapy, n = 2; or both, n = 1) prior to antiviral therapy. Of the 18 patients treated with IFN (Table 2), 8 received IFN alone and 10 received the IFN plus ribavirin combination, either because of partial or no response to IFN alone (n = 4) or as the first-line antiviral treatment (n = 6). Overall, 6 patients received associated therapy for severe symptomatic cryoglobulinemia (steroids, n = 6; cyclophosphamide, n = 3; and plasmapheresis n = 3). The mean duration of IFN and ribavirin therapy was 17 ± 9.1 months (range, 6-39 months) and 18.2 ± 7.2 months (range, 7-34 months), respectively.
Complete hematologic and virologic response was seen in 14 of 18 patients (78%). Mean time to hematologic response (decrease in lymphocyte counts) was 2.8 ± 2.7 months (range, 1-11 months).
There was a correlation between virologic and hematologic status because all patients who cleared HCV had a sustained hematologic response after a mean follow-up of 62.3 months. In one patient, relapse of SLVL coincided with reappearance of serum HCV RNA. Reinitiation of antiviral therapy led to a second complete response. Two patients who had a partial virologic response (> 2 logs reduction in HCV RNA) achieved a complete hematologic response, whereas the 2 patients who exhibited a lower reduction of HCV RNA levels had only a partial hematologic response. Clinical manifestations of MC subsided in all patients with a complete virologic response.
Improvement in liver fibrosis was noted in 4 patients who cleared HCV. Bone marrow biopsies were performed in 5 patients, showing nodular or interstitial infiltrates. After antiviral therapy, bone marrow infiltrates disappeared in 2 complete responders, whereas it remained in 3 patients with partial response.
Antiviral treatment was well tolerated (Table 2). During the follow-up 3 patients died. One 71-year-old complete responder died from myocardial infarction. Two partial responders, 63 and 38 years old, died from hepatocellular carcinoma and sepsis after 40 and 36 months, respectively.
In all 14 patients in whom molecular studies were performed, the monoclonal immunoglobulin gene rearrangement was still detectable in the blood even though a complete hematologic response was achieved. These findings contrast with previous reports stating the disappearance of B-cell clones in the blood of HCV-infected patients after antiviral therapy.14-16 This discrepancy may reflect differences in tumor load or in survival requirements. In the case of SLVL, some clones, though remaining antigen-dependent for their proliferation, may survive in the favorable environment of the spleen or bone marrow, even after effective clearance of HCV.
Our findings emphasize that antiviral therapy should be the first choice of treatment of HCV patients with SLVL. Severe symptomatic MC may initially require treatment with steroids, immunosuppressive drugs, or plasma exchange.17 In most cases, however, antiviral therapy led to the rapid disappearance of symptoms even when cryoglobulinemia and lymphoma were still undetectable. Recently, Levine et al reported effective therapy against HCV in a case of HCV-associated mantle cell lymphoma.18 Antiviral therapy may also induce complete remission of lymphoplasmatic lymphoma or immunocytoma16 and marginal zone lymphoproliferation.13,19,20
Taken together, these data support a mechanistic role for HCV the pathogenesis of a subset of SLVL. Moreover, HCV plus SLVL appears to be part of the spectrum of HCV-driven cryoglobulin-associated lymphoproliferative disorders.
Acknowledgements
The authors acknowledge J. P. Bronowicki (CHU Nancy), V. Eclache-Saudreau (hospital Jean Verdier, Bondy), C. Brechot (CHU Necker, Paris), T. Asselah (CHU Beaujon, Clichy), J. P. Hayman (hospital Tenon, Paris), J. J. Boffa (hospital Tenon, Paris), O. Lidove (hospital Bichat, Paris), P. Hausfater (hospital Pitie Salpetrière, Paris), K. Jondeau (hospital Cochin, Paris), and B. Delmas (hospital Paul Brousse, Villejuif) for their help in the care and follow-up of the patients.
Footnotes
Prepublished online as Blood First Edition Paper, September 7, 2004; DOI 10.1182/blood-2004-05-1711.
D.S. and F.S. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
References
Zuckerman E, Zuckerman T, Levine AM, et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med. 1997; 127: 423-428.
Silvestri F, Pipan C, Barillari G, et al. Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders. Blood. 1996;87: 4296-4301.
Mele A, Pulsoni A, Bianco E, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood. 2003; 102: 996-999.
Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin's lymphoma: systematic review and meta-analysis. Gastroenterology. 2003;125: 1723-1732.
Hausfater P, Cacoub P, Rosenthal E, et al. Hepatitis C virus infection and lymphoproliferative diseases in France: a national study. The GER-MIVIC Group. Am J Hematol. 2000;64: 107-111.
De Vita S, Sacco C, Sansonno D, et al. Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection. Blood. 1997;90: 776-782.
Luppi M, Longo G, Ferrari MG, et al. Additional neoplasms and HCV infection in low-grade lymphoma of MALT type. Br J Haematol. 1996;94: 373-375.
Troussard X, Valensi F, Duchayne E, et al. Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hematologie Cellulaire (GFHC). Br J Haematol. 1996;93: 731-736.
Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347: 89-94.
Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17: 3835-3849.
Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med. 1980;69: 287-308.
Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment virus C. Arthritis Rheum. 1999;42: 2204-2212.
Arcaini L, Paulli M, Boveri E, Magrini U, Lazzarino M. Marginal zone-related neoplasms of splenic and nodal origin. Haematologica. 2003;88: 80-93.
Giannelli F, Moscarella S, Giannini C, et al. Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation. Blood. 2003; 102: 1196-1201.
Zuckerman E, Zuckerman T, Sahar D, et al. The effect of antiviral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood. 2001;97: 1555-1559.
Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy. Cancer. 1996;77: 2604-2613.
Cacoub P, Lidove O, Maisonobe T, et al. Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum. 2002;46: 3317-3326.
Levine AM, Shimodaira S, Lai MM. Treatment of HCV-related mantle-cell lymphoma with ribavirin and pegylated interferon alfa. N Engl J Med. 2003; 349: 2078-2079.
Pitini V, Arrigo C, Righi M, Scaffidi M, Sturniolo G. Systematic screening for HCV infection should be performed in patients with splenic marginal zone lymphoma. Br J Haematol. 2004;124: 252-253.
Casato M, Mecucci C, Agnello V, et al. Regression of lymphoproliferative disorder after treatment for hepatitis C virus infection in a patient with partial trisomy 3, Bcl-2 overexpression, and type II cryoglobulinemia. Blood. 2002;99: 2259-2261.(David Saadoun, Felipe Sua)
Department of Rheumatology, hospital de Kremlin-Bicêtre, Le Kremlin-Bicêtre, France
Department of Hematology, CHU Cte de Nacre, Caen, France
Department of Internal Medicine, hospital Pitie-Salpetrière, Paris, France.
Abstract
Hepatitis C virus (HCV) has been associated with the development of B-cell non-Hodgkin lymphomas. We recently reported the regression of splenic lymphoma with villous lymphocytes (SLVL) in patients with HCV after antiviral treatment, demonstrating a direct role of HCV in lymphomagenesis. This study expands our previous results in 18 patients with chronic HCV and SLVL. Mixed cryoglobulinemia (MC) was present in all cases and was symptomatic in 13 (72%). All patients were treated with interferon alone or in association with ribavirin. Hematologic and virologic responses were correlated. Fourteen (78%) patients achieved a sustained complete hematologic response after clearance of HCV RNA. Two patients had a virologic partial response and achieved a complete hematologic response. Two virologic nonresponders achieved partial hematologic response. Regardless of the response, monoclonal immunoglobulin gene rearrangement persisted after treatment. This study underscores the role of HCV in the lymphomagenesis and the benefit of antiviral treatment for patients presenting with HCV-driven lymphoproliferations.
Introduction
Hepatitis C virus (HCV) is associated with a spectrum of extrahepatic manifestations, mainly mixed cryoglobulinemia (MC). MC-producing B cells are mostly monoclonal and a significant proportion of MCs can evolve into overt B-cell lymphoma. As such, HCV-MC is considered as a low-grade B-cell lymphoproliferative disorder. A link between HCV infection and B-cell non-Hodgkin lymphoma (NHL) has been suggested by many epidemiologic studies.1-3 In a meta-analysis, the prevalence of HCV infection in patients with B-cell NHL was 15% compared to 1.5% in the general population.4 Although most histologic subtypes of B-cell lymphomas have been described in association with HCV,5 lymphoplasmacytic lymphomas, marginal zone lymphomas (MZLs), and large B-cell lymphomas are more common in individuals infected with HCV.3,6,7 These epidemiologic studies establish the association between HCV infection and B-cell NHL but shed no light on the pathogenic role of the virus in the development of lymphomas.
Splenic lymphoma with villous lymphocytes (SLVL) is a chronic B-cell lymphoproliferative disorder characterized by a clonal expansion of atypical B lymphocytes with villous projections in peripheral blood. SLVL involves mainly the spleen and the bone marrow. Villous lymphocytes have immunologic and Immunophenotypical characters of marginal zone lymphocytes. SLVL is usually treated by splenectomy or chemotherapy or both, with an overall 5-year survival rate of 80%.8
We recently reported the regression of SLVL in patients with HCV after antiviral treatment,9 demonstrating a direct role of HCV in lymphomagenesis. The present study expands our previous results in a cohort of 18 patients with chronic HCV and SLVL.
Study design
Between 1993 and 2003, investigators from several French centers reported data on 18 patients with SLVL and HCV infection who were treated with antiviral therapy. Clinical and biologic data and outcome were analyzed. The diagnosis of SLVL was based on the presence of typical clinical, hematologic, and immunologic findings as previously described.8,10 All blood smears and immunophenotype findings were reviewed by 2 expert cytologists (F.V. and X.T.). Patients positive for MC were defined as having MC in their serum more than 0.05 g/L on at least 2 determinations. Symptomatic MC was defined by serum MC associated with the triad of purpura-arthralgia-asthenia and sometimes with renal or neurologic involvement.11
Patients received 3 million IU recombinant interferon-2b (IFN -2b), subcutaneously, 3 times a week for 6 months. In case of a partial response (> 50%), treatment was continued until a complete clinical response was achieved. In SLVL/HCV+ patients, diagnosed after 1996, ribavirin (1000-1200 mg/d) was added to IFN treatment.
Complete response was defined as disappearance of HCV RNA, the resolution of splenomegaly, a platelet count more than 100 x 109/L, an absolute neutrophil count more than 1 x 109/L, a hemoglobin level more than 10 g/dL, and the absence of circulating blood villous lymphocytes. Partial response was defined by a palpable but reduced spleen size by at least 50%, associated with an improvement of the blood hematologic parameters over baseline (> 50%) and detectable HCV RNA. Treatment failure and disease progression were defined as a persistent or progressive increase in the number of peripheral blood villous lymphocytes or splenomegaly, respectively. Relapse was defined as a progressive increase in the number of peripheral blood villous lymphocytes or increasing splenomegaly after an initial complete or partial response.
Results and discussion
All 18 patients had type II MC with symptoms of MC vasculitis in 13 (72%; Table 1), a much higher frequency than usually noted in cryoglobulin-positive HCV patients.12 Clinical symptoms of MC preceded the diagnosis of SLVL in 7 patients (mean of 3.5 years before SLVL diagnosis) and were contemporaneous in the other 6 patients. Except for the usual absence of clinical or biologic MC, and the lack of response to antiviral treatment, HCV– SLVL is similar to HCV-associated SLVL.8,9,13 The strong association of type II MC and HCV-associated SLVL is an important finding of this study. SLVL may be integrated in the spectrum of cryoglobulin associated B-cell proliferations.
HCV genotype 1 was observed in 7 of our patients. Despite of the usual resistance of this genotype to antiviral therapy, 4 of these patients achieved a complete hematologic response after INF and ribavirin.
Four patients had received a first-line therapy for SLVL (splenectomy, n = 2; chemotherapy, n = 2; or both, n = 1) prior to antiviral therapy. Of the 18 patients treated with IFN (Table 2), 8 received IFN alone and 10 received the IFN plus ribavirin combination, either because of partial or no response to IFN alone (n = 4) or as the first-line antiviral treatment (n = 6). Overall, 6 patients received associated therapy for severe symptomatic cryoglobulinemia (steroids, n = 6; cyclophosphamide, n = 3; and plasmapheresis n = 3). The mean duration of IFN and ribavirin therapy was 17 ± 9.1 months (range, 6-39 months) and 18.2 ± 7.2 months (range, 7-34 months), respectively.
Complete hematologic and virologic response was seen in 14 of 18 patients (78%). Mean time to hematologic response (decrease in lymphocyte counts) was 2.8 ± 2.7 months (range, 1-11 months).
There was a correlation between virologic and hematologic status because all patients who cleared HCV had a sustained hematologic response after a mean follow-up of 62.3 months. In one patient, relapse of SLVL coincided with reappearance of serum HCV RNA. Reinitiation of antiviral therapy led to a second complete response. Two patients who had a partial virologic response (> 2 logs reduction in HCV RNA) achieved a complete hematologic response, whereas the 2 patients who exhibited a lower reduction of HCV RNA levels had only a partial hematologic response. Clinical manifestations of MC subsided in all patients with a complete virologic response.
Improvement in liver fibrosis was noted in 4 patients who cleared HCV. Bone marrow biopsies were performed in 5 patients, showing nodular or interstitial infiltrates. After antiviral therapy, bone marrow infiltrates disappeared in 2 complete responders, whereas it remained in 3 patients with partial response.
Antiviral treatment was well tolerated (Table 2). During the follow-up 3 patients died. One 71-year-old complete responder died from myocardial infarction. Two partial responders, 63 and 38 years old, died from hepatocellular carcinoma and sepsis after 40 and 36 months, respectively.
In all 14 patients in whom molecular studies were performed, the monoclonal immunoglobulin gene rearrangement was still detectable in the blood even though a complete hematologic response was achieved. These findings contrast with previous reports stating the disappearance of B-cell clones in the blood of HCV-infected patients after antiviral therapy.14-16 This discrepancy may reflect differences in tumor load or in survival requirements. In the case of SLVL, some clones, though remaining antigen-dependent for their proliferation, may survive in the favorable environment of the spleen or bone marrow, even after effective clearance of HCV.
Our findings emphasize that antiviral therapy should be the first choice of treatment of HCV patients with SLVL. Severe symptomatic MC may initially require treatment with steroids, immunosuppressive drugs, or plasma exchange.17 In most cases, however, antiviral therapy led to the rapid disappearance of symptoms even when cryoglobulinemia and lymphoma were still undetectable. Recently, Levine et al reported effective therapy against HCV in a case of HCV-associated mantle cell lymphoma.18 Antiviral therapy may also induce complete remission of lymphoplasmatic lymphoma or immunocytoma16 and marginal zone lymphoproliferation.13,19,20
Taken together, these data support a mechanistic role for HCV the pathogenesis of a subset of SLVL. Moreover, HCV plus SLVL appears to be part of the spectrum of HCV-driven cryoglobulin-associated lymphoproliferative disorders.
Acknowledgements
The authors acknowledge J. P. Bronowicki (CHU Nancy), V. Eclache-Saudreau (hospital Jean Verdier, Bondy), C. Brechot (CHU Necker, Paris), T. Asselah (CHU Beaujon, Clichy), J. P. Hayman (hospital Tenon, Paris), J. J. Boffa (hospital Tenon, Paris), O. Lidove (hospital Bichat, Paris), P. Hausfater (hospital Pitie Salpetrière, Paris), K. Jondeau (hospital Cochin, Paris), and B. Delmas (hospital Paul Brousse, Villejuif) for their help in the care and follow-up of the patients.
Footnotes
Prepublished online as Blood First Edition Paper, September 7, 2004; DOI 10.1182/blood-2004-05-1711.
D.S. and F.S. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
References
Zuckerman E, Zuckerman T, Levine AM, et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med. 1997; 127: 423-428.
Silvestri F, Pipan C, Barillari G, et al. Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders. Blood. 1996;87: 4296-4301.
Mele A, Pulsoni A, Bianco E, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood. 2003; 102: 996-999.
Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin's lymphoma: systematic review and meta-analysis. Gastroenterology. 2003;125: 1723-1732.
Hausfater P, Cacoub P, Rosenthal E, et al. Hepatitis C virus infection and lymphoproliferative diseases in France: a national study. The GER-MIVIC Group. Am J Hematol. 2000;64: 107-111.
De Vita S, Sacco C, Sansonno D, et al. Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection. Blood. 1997;90: 776-782.
Luppi M, Longo G, Ferrari MG, et al. Additional neoplasms and HCV infection in low-grade lymphoma of MALT type. Br J Haematol. 1996;94: 373-375.
Troussard X, Valensi F, Duchayne E, et al. Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hematologie Cellulaire (GFHC). Br J Haematol. 1996;93: 731-736.
Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347: 89-94.
Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17: 3835-3849.
Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med. 1980;69: 287-308.
Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment virus C. Arthritis Rheum. 1999;42: 2204-2212.
Arcaini L, Paulli M, Boveri E, Magrini U, Lazzarino M. Marginal zone-related neoplasms of splenic and nodal origin. Haematologica. 2003;88: 80-93.
Giannelli F, Moscarella S, Giannini C, et al. Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation. Blood. 2003; 102: 1196-1201.
Zuckerman E, Zuckerman T, Sahar D, et al. The effect of antiviral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood. 2001;97: 1555-1559.
Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy. Cancer. 1996;77: 2604-2613.
Cacoub P, Lidove O, Maisonobe T, et al. Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum. 2002;46: 3317-3326.
Levine AM, Shimodaira S, Lai MM. Treatment of HCV-related mantle-cell lymphoma with ribavirin and pegylated interferon alfa. N Engl J Med. 2003; 349: 2078-2079.
Pitini V, Arrigo C, Righi M, Scaffidi M, Sturniolo G. Systematic screening for HCV infection should be performed in patients with splenic marginal zone lymphoma. Br J Haematol. 2004;124: 252-253.
Casato M, Mecucci C, Agnello V, et al. Regression of lymphoproliferative disorder after treatment for hepatitis C virus infection in a patient with partial trisomy 3, Bcl-2 overexpression, and type II cryoglobulinemia. Blood. 2002;99: 2259-2261.(David Saadoun, Felipe Sua)