Skip to main content

Splenic marginal zone lymphomas in acquired C1-inhibitor deficiency: clinical and molecular characterization


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.

This is a preview of subscription content, access via your institution.


  1. 1.

    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.

    Article  Google Scholar 

  2. 2.

    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

    Google Scholar 

  3. 3.

    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.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    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.

    Article  PubMed  CAS  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    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

    Article  PubMed  Google Scholar 

  7. 7.

    Teixeira Mendes LS, Wotherspoon A. Marginal zone lymphoma: Associated autoimmunity and auto-immune disorders. Best Pract. Res. Clin. Haematol. 2017;30:65–76.

    Article  PubMed  Google Scholar 

  8. 8.

    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.

    Article  CAS  Google Scholar 

  9. 9.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    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.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011;331:435–9.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    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.

    PubMed  CAS  Google Scholar 

  13. 13.

    Wu MA, Castelli R. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity. Clin. Chem. Lab. Med. 2016;54:207–214.

    PubMed  CAS  Google Scholar 

  14. 14.

    Spina V, Rossi D. Molecular pathogenesis of splenic and nodal marginal zone lymphoma. Best Pract. Res. Clin. Haematol. 2017;30:5–12.

    Article  PubMed  Google Scholar 

  15. 15.

    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.

    Article  CAS  Google Scholar 

  16. 16.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    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.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Roberto Castelli.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individuals participants included in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


  • Acquired angioedema (AAE)
  • Lymphoproliferative disease
  • Splenic marginal zone lymphoma (SMZL)
  • NOTCH2 mutation
  • Restricted immunoglobulin gene repertoire analysis