Angioedema due to acquired deficiency of the inhibitor of the first component of complement (C1-INH) is a rare disease known as acquired angioedema (AAE). About 70% of patients with AEE display autoantibodies to C1-INH, the remaining patients have no antibodies to C1-INH. The clinical features of C1-INH deficiency include recurrent, self-limiting local swellings involving the skin, the gastrointestinal tract, and the upper respiratory tract. Swelling is due to accumulation of bradykinin released from high molecular weight kininogen. Patients with angioedema due to acquired C1 inhibitor deficiency (AEE) often have an associated lymphoproliferative disease including Non-Hodgkin Lymphomas (NHL). Among AAE patients with NHL, splenic marginal zone lymphoma (SMZL) has a higher prevalence (66%) compared to general population (2%) In the present study, we focused on patients with SMZL in AAE. We found 24 AAE patients with NHL and, among them 15 SMZL (62.5% of all NHL). We found NOTCH 2 activation in 4 /15 patients (26.6%) with SMZL, while no patients carried MYD 88 or BIRC3 mutations. Restricted immunoglobulin gene repertoire analysis showed that the IGHV1-2*04 allele was found to be over-represented in the group of patients with or without lymphoproliferative disease presenting with autoantibodies to C1-INH (41 of 55 (75%) of patients; p value 0.011) when compared to the control group of patients with AEE without antibodies to C1-INH, (7 of 27 (26%) of patients). Immunophenotyping failed to demonstrate the presence of autoreactive clones against C1-inhibitor. Taken together, these findings suggest a role for antigenic stimulation in the pathogenesis of lymphomas associated with AEE.
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Castelli R, Zanichelli A, Cicardi M, et al. Acquired C1-inhibitor deficiency and lymphoproliferative disorders: a tight relationship. Crit. Rev. Oncol. Hematol. 2013;87(3):323–332.
Castelli R, Zanichelli A, Cugno M. Therapeutic options for patients with angioedema due to C1-inhibitor deficiencies: from pathophysiology to the clinic. Imm unopharmacol. Immunotoxicol. 2013;35:181–190
Suffritti C, Zanichelli A, Maggioni L, et al. High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency. Clin Exp Allergy. 2014;44:1503–14.
Caccia S, Castelli R, Maiocchi D, et al. Interaction of C1 inhibitor with thrombin on the endothelial surface. Blood Coagul Fibrinolysis. 2011;22:571–5.
Cugno M, Castelli R, Cicardi M. Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and lymphoproliferation. Autoimmun. Rev. 2008;8(2) 156–159.
Castelli R, Wu MA, Arquati M, et al. High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibtor deficiency. Br. J. Haematol. 2016;172:902–908
Teixeira Mendes LS, Wotherspoon A. Marginal zone lymphoma: Associated autoimmunity and auto-immune disorders. Best Pract. Res. Clin. Haematol. 2017;30:65–76.
Castelli R, Bergamaschini L, Deliliers GL. First-line treatment with bendamustine and rituximab, in patients with intermediate-/high-risk splenic marginal zone lymphomas. Med. Oncol. 2018;35;15.
Castelli R, Gidaro A, Deliliers GL. Bendamustine and rituximab, as first line treatment, in intermediate, high risk splenic marginal zone lymphomas of elderly patients. Mediterr J Hematol Infect Dis. 2016;8:e2016030.
Alsenz J, Loos M. A rapid and simple ELISA for the determination of duplicate monoclonal antibodies during epitope analysis of antigens and its application to the study of C1(-)-INH. J Immunol Methods. 1988;109:75–84.
Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011;331:435–9.
Gattei V, Degan M, Gloghini A, et al. CD30 ligand is frequently expressed in human hematopoietic malignancies of myeloid and lymphoid origin. Blood. 1997;89:2048–59.
Wu MA, Castelli R. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity. Clin. Chem. Lab. Med. 2016;54:207–214.
Spina V, Rossi D. Molecular pathogenesis of splenic and nodal marginal zone lymphoma. Best Pract. Res. Clin. Haematol. 2017;30:5–12.
Brisou G, Verney A, Wenner T, et al. Letters to the editor: a restricted IGHV gene repertoire in splenic marginal zone lymphoma is associated with autoimmune disorders. Haematologica. 2014;99(e198):197–8.
Arcaini L, Rossi D, Lucioni M, et al. The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection. Haematologica. 2015;100:246–52.
Bikos V, Karypidou M, Stalika E, et al. An immunogenetic signature of ongoing antigen interactions in splenic marginal zone lymphoma expressing IGHV1-2*04 receptors. Clin Cancer Res. 2016;22:2032–40.
Fonte E, Agathangelidis A, Reverberi D, et al. Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation. Haematologica. 2015;100:1460–8.
Visentini M, Conti V, Cristofoletti C, et al. Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity. Autoimmun Rev. 2013;12:430–5.
Conflict of interest
All authors declare that they have no conflict of interest.
Informed consent was obtained from all individuals participants included in the study.
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Sbattella, M., Zanichelli, A., Ghia, P. et al. Splenic marginal zone lymphomas in acquired C1-inhibitor deficiency: clinical and molecular characterization. Med Oncol 35, 118 (2018). https://doi.org/10.1007/s12032-018-1183-7
- Acquired angioedema (AAE)
- Lymphoproliferative disease
- Splenic marginal zone lymphoma (SMZL)
- NOTCH2 mutation
- Restricted immunoglobulin gene repertoire analysis