High Prevalence of Marginal ZONE Lymphoma Among Patients with Acquired C1- Inhibtor Deficiency

Background: Lymphoma of the marginal zone, represent less than 10% of al non Hodgkin lymphoma (NHL). Nevertheless, they are the predominant form of lymphoma associated with angioedema due to acquired C1-inhibitor deficiency (C1-INH-AAE). In this rare condition C1-INH is consumed mainly due to the presence of neutralizing autoantibodies to this protein. Interestingly, 30% of patients with C1-INH-AAE have or develop NHL, which in the large majority derives from the marginal zone. The clinical features of C1-INH deficiency, which more commonly is of genetic origin (hereditary angioedema HAE), include recurrent, self-limiting local swellings involving the upper respiratory tract and the gastrointestinal tract. Swelling is due to local accumulation of bradykinin released from high molecular weight kininogen upon uncontrolled activation of plasma kallikrein. The etiology of acquired C1-INH deficiency remains undefined, but the majority of patients carry an underlying B-cell disorders. These B-cell disorders range from production of anti-C1-INH autoantibodies to monoclonal gammopathies of uncertain significance (MGUS) to Non Hodgkin Lymphomas (NLHs) Growing experimental evidence suggests that microenvironmental interactions driven by inflammatory and infectious conditions favor development or promotion of specific subtypes of indolent non-follicular NHL (marginal zone lymphomas, MZLs; lymphoplasmatycic lymphomas, LPLs ;small lymphocytic lymphomas, SLLs). This evidence suggests a role for chronic immune stimulation, either from persistent microbial infections or to autoantigens, in B cell transformation. Here we report data from 72 C1-INH-AAE patients associated to NHL in 24. Most NHL are indolent non follicular B cells lymphoproliferative disease (INFBCLs,) suggesting a likely antigen-driven pathogenetic mechanism.

Patients and Methods: Seventy-two AAE patients were included.The diagnosis was based on a history of recurrent angioedema , which began during or after the fourth decade of life, absence of family history of angioedema, and detection of C1-INH functional levels below 50% of normal.Serum or plasma samples were stored at -80°C until tested. C1-INH, C4, C3, and C1q antigens were measured by radial immunodiffusion. C1-INH antigenic and C4 were quantified using radial immunodiffusion or nephelometry; C1-INH function was measured using an immunoenzimatic assay. Autoantibodies to C1-INH in serum were measured by enzyme-linked immunosorbent assay Hematoxyllin–eosin stained slides were reviewed. Lymphoprolipherative disorders were classified according to the WHO classification.

Results: Overall, 33.3% (24/72) of AAE patients had an underlying B-cell NHL. Most NHL (62,5%, 15/24) were diagnosed at onset of AAE or thereafter (3 months to 7 years), while in the remaining cases were diagnosed before the onset of AEE symptoms. According to the WHO classification, 29% (21/72) patients had indolent NHL and 4% (3/72) aggressive NHL (1 diffuse large B-cell lymphoma and 2 mantle cell lymphoma).Among patients with indolent NHL, most had splenic MZL (71%, 15/21), while the remaining had had LPL (n=3), SLL (n=2), or follicular lymphoma (n=1) .Serological evidence of hepatitis C virus infection was reported in 1 of 24 patients. Autoantibodies to C1-INH were detected in 54% (13/24) patients, including 12/15 ( 80%)  of cases with a diagnosis of SMZL.Of the 20 patients with indolent B cell lymphoprolipherative disease 13/20 received systemic therapy. Chemotherapy was performed in 13/24 patients (2 R-CHOP,1 Rituximab –fludarabine,1 Chlorambucil, 5 Bendamustine R, 2 R-CVP, 2 CFX/Prednisone).Splenectomy without chemotherapy  was performed in 3; 2 patients were treated with Rituximab alone. Thirteen patients experienced complement improvement or reduction in AAE symptoms after chemotherapy. Four patients received no therapy.

Conclusions: Our series is the largest reported to date and confirms that SMZL represents the most common histotype among AAE patients, with a frequency of 75% of INFBCL (15/20 indolent lymphoprolipherative disease) and of 62.5% of all lymphoprolipherative diseases identified.The post-germinal center origin of most of NHLs suggests that immune stimulation may contribute to lymphomagenesis.