Non-Hodgkin’s Lymphoma May Be Cause of Acquired Angioedema: Case

Study cites lymphoma as possible trigger in case of healthy man

Teresa Carvalho, MS avatar

by Teresa Carvalho, MS |

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A splenic marginal zone lymphoma (SMZL) — a type of non-Hodgkin’s lymphoma that involves the spleen, bone marrow, and blood — might have triggered acquired angioedema in a man in his 60s, a case study reported.

“The occurrence of [non-Hodgkin’s] lymphoma in association with [acquired angioedema] grossly exceeds that expected for overall incidence,” or the rate of new disease cases over a specified period of time, the researchers wrote.

Non-Hodgkin’s lymphoma “is found in up to 33% of cases of [acquired angioedema], with up to 66% of these cases being SMZL,” the team added.

The case study, “Acquired angioedema: an unusual presentation of haematological malignancy,” was published in the journal BMJ Case Reports.

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Swelling in the deeper layers of the skin characterizes angioedema, a condition that may have several causes — among them allergies, reactions to medications, and genetic mutations.

Angioedema is typically associated with low blood levels of a protein called C1-inhibitor (C1-INH). This protein controls the levels of C1 protein, which is part of the immune system and plays a role in the body’s inflammatory response.

Lymphoma and acquired angioedema

There are different types of angioedema based on the underlying causes and the blood levels of C1-INH. In one of these types, called acquired angioedema, the body’s immune system erroneously produces antibodies targeting C1-INH.

This antibody formation may be due to an autoimmune condition or a lymphoproliferative disorder — a blood condition characterized by the uncontrolled growth of white blood cells. Regardless of type, low levels of C1-INH lead to increased levels of bradykinin, a molecule that plays a crucial role in inflammation. High levels of bradykinin in turn trigger swelling.

A team of researchers from Malta now reported the case of a sexagenarian who had frequent angioedema attacks triggered by a SMZL, a type of lymphoproliferative disorder.

The man was referred to the hospital after spleen enlargement was observed by his family doctor. The patient had recently started treatment with esomeprazole, a medication used for gastro-esophageal reflux.

Soon after, he experienced swelling in the eyes and mouth. He was admitted to the emergency unit and given hydrocortisone, a corticosteroid medication, and oral antihistamines, an anti-allergic medicine. He went home and was treated with another corticosteroid, called prednisolone, for two weeks.

About a month later, a sample of his bone marrow was collected to analyze the presence of B-cells — a type of cells involved in the body’s immune response — as part of a regular workup for spleen enlargement. However, these cells were not observed. As such, and given his enlarged spleen, tissue samples of the organ were collected, which showed mild signs of inflammation.

A few months later, the man returned to the hospital because his tongue had swollen after eating fish. Symptoms eased after treatment with hydrocortisone and another anti-allergic medication, and he returned home.

Two weeks later, lip swelling reappeared and the patient was given hydrocortisone and discharged. Hours later, he returned to the emergency room with difficulty breathing, and was hospitalized for investigation and monitoring.

An examination revealed swelling in the throat. C1-INH activity levels were checked and appeared to be low (less than 25%). The patient again returned home and continued treatment with anti-allergic medications.

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Scientists: Trials needed into SMZL

A new bone marrow sample was collected and showed signs of B-cell infiltration. Because low C1-INH levels were found, the man was diagnosed with an acquired form of C1-INH deficiency resulting from a B-cell lymphoproliferative disorder — in this case, SMZL.

His enlarged spleen led researchers to suspect acquired C1-INH angioedema secondary to a possible lymphoproliferative disorder. The SZML diagnosis was then confirmed by a PET/CT scan.

According to researchers, hereditary angioedema was excluded due to the patient’s lack of family history or previous attacks.

Additionally, angioedema appeared to respond to steroids and antihistamines, initially pointing to a possible allergic origin. However, according to the team, steroid administration likely produced an immune response in the patient due to the excessive B-cell proliferation characteristic of SMZL. As such, steroids had the “ dual effect of masking the bradykinin-induced angioedema typical of C1-INH deficiency” and thus making diagnosis difficult.

“Given the lack of family history, response to steroids and coexistence of splenomegaly [enlarged spleen], a lymphoproliferative disorder-induced acquired C1-INH deficiency was favored,” they wrote.

“This case emphasizes both the importance of considering an acquired cause of C1-INH deficiency for unexplained angioedema, as well as the need for a high index of suspicion for a B-cell lymphoproliferative disorder, even when bone marrow aspirate … [is] seemingly normal,” they wrote.

A plasma-derived C1-INH concentrate was given to prevent future swelling attacks and SMZL was treated with rituximab, a B-cell depleting antibody-based therapy.

Spleen size diminished, autoantibodies went away, and C1-INH activity levels normalized. No further attacks occurred once rituximab was started.

However, there are no official guidelines on the treatment of SMZL with C1-INH deficiency. As such, researchers stressed that “further clinical trials in SMZL associated AAE [acquired angioedema] are therefore warranted.”