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

Sbattella, Matteo; Zanichelli, Andrea; Gattei, Valter; Suffritti, Chiara; Teatini, Thomas; Cicardi, Marco; Castelli, Roberto

doi:10.1007/s12032-018-1183-7

Cited by 20 publications

(16 citation statements)

References 21 publications

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“…Reports of series of patients with AAE-C1-INH revealed underlying B-cell disorders including monoclonal gammopathies of uncertain significance and non-Hodgkin lymphomas (NHLs) in one-third of the patients [8,[21][22][23]. SMZL has been identified as the most common condition in patients with AAE-C1-INH, representing 54-62% of the non-Hodgkin lymphomas identified [22,23]. Case reports have also raised awareness of the association of AAE-C1-INH with SMZL [24][25][26].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

Ferriani

Trevisan-Neto

Costa

et al. 2020

Int Arch Allergy Immunol

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Background: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. Objectives: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. Methods: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. Results: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. Conclusions: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.

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Section: Discussion/conclusionmentioning

confidence: 99%

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

Ferriani

Trevisan-Neto

Costa

et al. 2020

Int Arch Allergy Immunol

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“…Little is known about the cellular events triggering anti‐C1INH production in AAE, although the latest evidence suggests that antigenic stimulation of B cells, either from persistent microbial infections or from autoantigens, plays a prominent role as indicated by over‐representation of the IGHV1‐2*04 immunoglobulin allele in those AAE patients with detectable free autoantibodies . How autoreactive B cells modulate anti‐C1INH levels is not known.…”

Section: Discussionmentioning

confidence: 99%

“…B cell proliferation, frequently with clonal characteristics, is associated with acquired C1INH deficiency and can be responsible for the production of the neutralizing antiC1INHAbs, as well as for an increased risk of lymphoproliferative disease . Lymphoproliferation in AAE ranges from monoclonal gammopathy of uncertain significance (MGUS) to non‐Hodgkin lymphomas, and it has been suggested that this pathological spectrum may reflect evolutionary stages of the same process, starting from expansion of anti‐C1INH autoreactive clones .…”

Section: Introductionmentioning

confidence: 99%

Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema

López-Lera

Garrido

Nozal

et al. 2019

Clinical and Experimental Immunology

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Acquired angioedema due to C1-inhibitor (C1INH) deficiency (AAE) is caused by secondary C1INH deficiency leading to bradykinin-mediated angioedema episodes. AAE typically presents in adulthood and is associated with B cell lymphoproliferation. Anti-C1INH autoantibodies (antiC1INHAbs) are detectable in a subset of AAE cases and considered a hallmark of the disease. When free antiC1INHAbs and malignant tumors are not detectable, diagnosis relies on the finding of low C1INH levels and/or function, lack of family history and SERPING1 mutations, age at onset and low or undetectable C1q levels, none of which is specific for AAE. We tested the diagnostic value of a novel enzyme-linked immunosorbent assay (ELISA) for the detection of circulating complexes between C1INH and antiC1INHAbs (C1INH-antiC1INHAb) in the serum of 20 European AAE patients characterized on the basis of their complement levels and function. Free antiC1INHAbs were detected in nine of 20 patients [six of immunoglobulin (Ig)G class, two of IgM class and one simultaneously presenting IgG and IgM classes], whereas C1INH-antiC1IN-HAb complexes were found in 18 of 20 of the AAE cases, regardless of the presence or absence of detectable free anti-C1INHAbs. Of note, nine of 20 patients showed negative free antiC1INHabs, but positive C1INH-antiC1INHAb complexes in their first measurement. In the cohort presented, IgM-class C1INH-antiC1INHAb are specifically and strongly associated with low C1q serum levels. Detection of C1INH-antiC1-INHAbs provides an added value for AAE diagnosis, especially in those cases in whom no free anti-C1INH antibodies are detected. The link between IgM-class C1INH-antiC1INHAb complexes and C1q consumption could have further implications for the development of autoimmune manifestations in AAE.

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“…According to the World Health Organization’s classification system, the most frequent histotypes of malignancies in patients with acquired C1-inhibitor deficiency are nodal and splenic marginal zone lymphomas and lymphoplasmacytic lymphomas/Waldenström’s disease [14]. SMZL is typically a rare disorder, comprising less than 2% of all lymphoid malignancies [15], but its prevalence is remarkably higher among AAE patients (66%) [16]. The prevalence of monoclonal gammopathy of uncertain significance in patients with acquired C1-inhibitor deficiency is 35%, which is much higher than its prevalence (approximately 3%) in the general population under age 70 years [17].…”

Section: Discussionmentioning

confidence: 99%

A Case of Acquired Angioedema with Low C1 Inhibitor (C1-INH) Associated with Splenic Marginal Zone Lymphoma

Abdel-Samad

Kokai

2019

Am J Case Rep

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Patient: Male, 68Final Diagnosis: AAESymptoms: AngioedemaMedication: —Clinical Procedure: —Specialty: HematologyObjective:Rare co-existance of disease or pathologyBackground:Angioedema is a vascular reaction of the soft tissues or mucosa, with localized increased permeability of blood vessels. Patients with late-onset angioedema without urticaria have an increased risk of non-Hodgkin lymphoma. We present a case of late-onset angioedema that demonstrates that it is sometimes necessary to treat an indolent malignancy to address the symptoms of a secondary condition.Case Report:A 68-year-old man presented to the Emergency Department with distressing swelling of his tongue and lips. No urticaria was observed and the remainder of the physical examination was unremarkable. The patient’s past medical history included chronic thrombocytopenia for the last 1.5 years, which had been asymptomatic. Routine laboratory testing revealed pancytopenia. The patient was referred to the Oncology Department, where he was diagnosed with splenic marginal zone lymphoma. A careful review of the patient’s past medical history revealed 3 episodes of soft tissue swelling of the lower limbs and 2 episodes of unexplained colicky abdominal pain. The patient was started on maintenance therapy of danazol, which prevented further episodes of angioedema. He later underwent splenectomy to improve his pancytopenia and to treat his lymphoma. In the postoperative period, the patient discontinued the danazol therapy. Three months after the splenectomy, he was asymptomatic and had not had any further angioedema episodes, and his laboratory values showed he was in remission.Conclusions:In this case, late-onset angioedema with recurrent episodes of soft tissue swelling was associated with underlying hematologic malignancy. The patient’s angioedema resolved when the malignancy was treated.

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

Cited by 20 publications

References 21 publications

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema

A Case of Acquired Angioedema with Low C1 Inhibitor (C1-INH) Associated with Splenic Marginal Zone Lymphoma

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