Characterization of B cell lymphoma in patients with Sjögren's syndrome and hepatitis C virus infection
Corresponding Author
Manuel Ramos-Casals
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Servei de Malalties Autoimmunes, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, SpainSearch for more papers by this authorFrancisco Medina
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorPaola Caramaschi
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorArmando Lopez-Guillermo
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorJosep Font
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
S. Martino Hospital, Oristano, Italy
University of Udine, Udine, Italy
Hospital Vall d'Hebron, Barcelona, Spain
University of Modena, Modena, Italy
Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Mexico DF, Mexico
University of Verona, Verona, Italy
Dr. Font is deceased.
Search for more papers by this authorCorresponding Author
Manuel Ramos-Casals
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Servei de Malalties Autoimmunes, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, SpainSearch for more papers by this authorFrancisco Medina
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorPaola Caramaschi
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorArmando Lopez-Guillermo
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorJosep Font
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain
S. Martino Hospital, Oristano, Italy
University of Udine, Udine, Italy
Hospital Vall d'Hebron, Barcelona, Spain
University of Modena, Modena, Italy
Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Mexico DF, Mexico
University of Verona, Verona, Italy
Dr. Font is deceased.
Search for more papers by this authorAbstract
Objective
To characterize the clinical and immunologic patterns of expression, response to therapy, and outcome of patients with Sjögren's syndrome (SS) and associated hepatitis C virus (HCV) infection who developed B cell lymphoma.
Methods
Various international reference centers constituted a multicenter study group with the purpose of creating a registry of patients with SS-HCV who developed B cell lymphoma. A protocol form was used to record the main characteristics of SS, chronic HCV infection, and B cell lymphoma.
Results
Twenty-five patients with SS-HCV with B cell lymphoma were included in the registry. There were 22 (88%) women and 3 (12%) men (mean age 55, 58, and 61 years at SS, HCV infection, and lymphoma diagnosis, respectively). The main extraglandular SS manifestations were cutaneous vasculitis in 15 (60%) patients and peripheral neuropathy in 12 (48%); the main immunologic features were positive rheumatoid factor (RF) in 24 (96%) and type II cryoglobulins in 20 (80%). The main histologic subtypes were mucosa-associated lymphoid tissue (MALT) lymphoma in 11 (44%) patients, diffuse large B cell lymphoma in 6 (24%), and follicular center cell lymphoma in 6 (24%). Fifteen (60%) patients had an extranodal primary location, most frequently in the parotid gland (5 patients), liver (4 patients), and stomach (4 patients). Twelve (52%) of 23 patients died after a median followup from the time of lymphoma diagnosis of 4 years, with lymphoma progression being the most frequent cause of death. Survival differed significantly between the main types of B cell lymphoma.
Conclusion
Patients with SS-HCV and B cell lymphoma are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver, and stomach).
REFERENCES
- 1 Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of Sjogren syndrome [review]. Arch Intern Med 2004; 164: 1275–84.
- 2 Ramos-Casals M, Tzioufas AG, Font J. Primary Sjogren's syndrome: new clinical and therapeutic concepts [review]. Ann Rheum Dis 2005; 64: 347–54.
- 3 Ramos-Casals M, Font J. Primary Sjogren's syndrome: current and emergent aetiopathogenic concepts [review]. Rheumatology (Oxford) 2005; 44: 1354–67.
- 4 Ramos-Casals M, Loustaud-Ratti V, de Vita S, Zeher M, Bosch JA, Toussirot E, et al, and the SS-HCV Study Group. Sjogren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine (Baltimore) 2005; 84: 81–9.
- 5 Zuckerman E, Zuckerman T. Hepatitis C and B-cell lymphoma: the hemato-hepatologist linkage [review]. Blood Rev 2002; 16: 119–25.
- 6 Ramos-Casals M, Font J. Extrahepatic manifestations in patients with chronic hepatitis C virus infection [review]. Curr Opin Rheumatol 2005; 17: 447–55.
- 7 Ramos-Casals M, Trejo O, Garcia-Carrasco M, Cervera R, de la Red G, Gil V, et al. Triple association between hepatitis C virus infection, systemic autoimmune diseases, and B cell lymphoma [review]. J Rheumatol 2004; 31: 495–9.
- 8 Selva-O'Callaghan A, Rodriguez-Pardo D, Sanchez-Sitjes L, Matas-Pericas L, Solans-Laque R, Bosch-Gil JA, et al. Hepatitis C virus infection, Sjögren's syndrome, and non-Hodgkin's lymphoma. Arthritis Rheum 1999; 42: 2489–90.
- 9 Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri G, Bencivelli W, Bernstein RM, et al. Preliminary criteria for the classification of Sjogren's syndrome: results of a prospective concerted action supported by the European community. Arthritis Rheum 1993; 36: 340–7.
- 10 Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization classification of tumors: pathology and genetics of tumors of hematopoietic and lymphoid tissues. Lyon: IARC Press; 2001.
- 11 Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al, and the NCI Sponsored International Working Group. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas [published erratum appears in J Clin Oncol 2000;18:2351]. J Clin Oncol 1999; 17: 1244–53.
- 12 Sansonno D, Lauletta G, de Re V, Tucci FA, Gatti P, Racanelli V, et al. Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection. Eur J Immunol 2004; 34: 126–36.
- 13 Morton LM, Engels EA, Holford TR, Leaderer B, Zhang Y, Zahm SH, et al. Hepatitis C virus and risk of non-Hodgkin lymphoma: a population-based case-control study among Connecticut women. Cancer Epidemiol Biomarkers Prev 2004; 13: 425–30.
- 14 Starkebaum G, Sasso EH. Hepatitis C and B cells: induction of autoimmunity and lymphoproliferation may reflect chronic stimulation through cell-surface receptors. J Rheumatol 2004; 31: 416–8.
- 15 Rabkin CS, Tess BH, Christianson RE, Wright WE, Waters DJ, Alter HJ, et al. Prospective study of hepatitis C viral infection as a risk factor for subsequent B-cell neoplasia. Blood 2002; 99: 4240–2.
- 16
Ohsawa M,
Shingu N,
Miwa H,
Yoshihara H,
Kubo M,
Tsukuma H, et al.
Risk of non-Hodgkin's lymphoma in patients with hepatitis C virus infection.
Int J Cancer
1999;
80:
237–9.
10.1002/(SICI)1097-0215(19990118)80:2<237::AID-IJC12>3.0.CO;2-I CAS PubMed Web of Science® Google Scholar
- 17 Hausfater P, Cacoub P, Sterkers Y, Thibault V, Amoura Z, Nguyen L, et al. Hepatitis C virus infection and lymphoproliferative diseases: prospective study on 1,576 patients in France. Am J Hematol 2001; 67: 168–71.
- 18 Arrieta JJ, Rodriguez-Inigo E, Ortiz-Movilla N, Bartolome J, Pardo M, Manzarbeitia F, et al. In situ detection of hepatitis C virus RNA in salivary glands. Am J Pathol 2001; 158: 259–64.
- 19 De Vita S, de Re V, Sansonno D, Sorrentino D, Corte RL, Pivetta B, et al. Gastric mucosa as an additional extrahepatic localization of hepatitis C virus: viral detection in gastric low-grade lymphoma associated with autoimmune disease and in chronic gastritis. Hepatology 2000; 31: 182–9.
- 20 Authier FJ, Bassez G, Payan C, Guillevin L, Pawlotsky JM, Degos JD, et al. Detection of genomic viral RNA in nerve and muscle of patients with HCV neuropathy. Neurology 2003; 60: 808–12.
- 21 Ducoulombier D, Roque-Afonso AM, di Liberto G, Penin F, Kara R, Richard Y, et al. Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes. Hepatology 2004; 39: 817–25.
- 22 Vallat L, Benhamou Y, Gutierrez M, Ghillani P, Hercher C, Thibault V, et al. Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. Arthritis Rheum 2004; 50: 3668–78.
- 23 Verbaan H, Carlson J, Eriksson S, Larsson A, Liedholm R, Manthorpe R, et al. Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjogren's syndrome and hepatitis C in Swedish patients. J Intern Med 1999; 245: 127–32.
- 24 Taliani G, Celestino D, Badolato MC, Pennica A, Bozza A, Poliandri G, et al. Hepatitis C virus infection of salivary gland epithelial cells: lack of evidence. J Hepatol 1997; 26: 1200–6.
- 25 Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette JC, et al, and the MULTIVIRC Group. Extrahepatic manifestations of chronic hepatitis C. Arthritis Rheum 1999; 42: 2204–12.
- 26 Mariette X. Lymphomas complicating Sjogren's syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells. Ann Rheum Dis 2001; 60: 1007–10.
- 27 De Re V, de Vita S, Gasparotto D, Marzotto A, Carbone A, Ferraccioli G, et al. Salivary gland B cell lymphoproliferative disorders in Sjogren's syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkin's lymphomas. Eur J Immunol 2002; 32: 903–10.
- 28 King PD, McMurray RW, Becherer PR. Sjogren's syndrome without mixed cryoglobulinemia is not associated with hepatitis C virus infection. Am J Gastroenterol 1994; 89: 1047–50.
- 29 Ramos-Casals M, Jara LJ, Medina F, Rosas J, Calvo-Alen J, Mana J, et al, and the HISPAMEC Study Group. Systemic autoimmune diseases co-existing with chronic hepatitis C virus infection (the HISPAMEC Registry): patterns of clinical and immunological expression in 180 cases. J Intern Med 2005; 257: 549–57.
- 30 Fox RI. Sjogren's syndrome. Lancet 2005; 366: 321–31.
- 31 Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM. Malignant lymphoma in primary Sjogren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjogren's Syndrome. Arthritis Rheum 1999; 42: 1765–72.
- 32 Ramos-Casals M, Cervera R, Yague J, Garcia-Carrasco M, Trejo O, Jimenez S, et al. Cryoglobulinemia in primary Sjogren's syndrome: prevalence and clinical characteristics in a series of 115 patients. Semin Arthritis Rheum 1998; 28: 200–5.
- 33 Theander E, Manthorpe R, Jacobsson LT. Mortality and causes of death in primary Sjogren's syndrome: a prospective cohort study. Arthritis Rheum 2004; 50: 1262–9.
- 34 Tzioufas AG, Boumba DS, Skopouli FN, Moutsopoulos HM. Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren's syndrome. Arthritis Rheum 1996; 39: 767–72.
- 35 Dorner T, Egerer K, Feist E, Burmester GR. Rheumatoid factor revisited [review]. Curr Opin Rheumatol 2004; 16: 246–53.
- 36 Mazzaro C, Tirelli U, Pozzato G. Hepatitis C virus and non-Hodgkin's lymphoma 10 years later [review]. Dig Liver Dis 2005; 37: 219–26.
- 37 De Vita S, Sacco C, Sansonno D, Gloghini A, Dammacco F, Crovatto M, et al. Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection. Blood 1997; 90: 776–82.
- 38 Ferri C, Caracciolo F, Zignego AL, la Civita L, Monti M, Longombardo G, et al. Hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Br J Haematol 1994; 88: 392–4.
- 39 Monti G, Pioltelli P, Saccardo F, Campanini M, Candela M, Cavallero G, et al. Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005; 165: 101–5.
- 40 Dammacco F, Sansonno D, Piccoli C, Tucci FA, Racanelli V. The cryoglobulins: an overview [review]. Eur J Clin Invest 2001; 31: 628–38.
- 41 Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 2005; 64: 913–20.
- 42 Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, et al. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience. J Clin Oncol 2005; 23: 468–73.
- 43 Salam I, Durai D, Murphy JK, Sundaram B. Regression of primary high-grade gastric B-cell lymphoma following Helicobacter pylori eradication. Eur J Gastroenterol Hepatol 2001; 13: 1375–8.
- 44 Furman RR, Coleman M, Leonard JP. Epratuzumab in non-Hodgkin's lymphomas [review]. Curr Treat Options Oncol 2004; 5: 283–8.
- 45 Zaja F, de Vita S, Mazzaro C, Sacco S, Damiani D, de Marchi G, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003; 101: 3827–34.
- 46 Tursi A, Brandimarte G, Torello M. Disappearance of gastric mucosa-associated lymphoid tissue in hepatitis C virus-positive patients after anti-hepatitis C virus therapy. J Clin Gastroenterol 2004; 38: 360–3.
- 47 Saadoun D, Suarez F, Lefrere F, Valensi F, Mariette X, Aouba A, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood 2005; 105: 74–6.
- 48 Kelaidi C, Rollot F, Park S, Tulliez M, Christoforov B, Calmus Y, et al. Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia 2004; 18: 1711–6.
- 49 Iannitto E, Ambrosetti A, Ammatuna E, Colosio M, Florena AM, Tripodo C, et al. Splenic marginal zone lymphoma with or without villous lymphocytes: hematologic findings and outcomes in a series of 57 patients. Cancer 2004; 101: 2050–7.
