Acquired angiodema may be first sign of underlying lymphoma
Case study: Treatment led to an almost complete remission of blood cancer type
Acquired angioedema was the first sign of an underlying extranodal marginal zone lymphoma (EMZL) — a type of non-Hodgkin lymphoma — in a 45-year-old woman, according to a case study.
After a comprehensive evaluation involving cancer and immunology specialists, she received treatment with rituximab. The therapy resolved her angioedema symptoms and led to an almost complete remission of the underlying lymphoma.
“Acquired angioedema (AAE) is tightly linked to lymphoproliferative disorders,” researchers wrote. “Early recognition and a multidisciplinary approach are essential for management and treating of underlying causes of AAE.”
The case study, “Acquired Angioedema as the First Sign of Lymphoproliferative Disorder: Case Report and Review of Literature,” was published in the Journal of Primary Care & Community Health.
Angioedema characterized by swelling in deeper skin layers
Angioedema is characterized by swelling in the deeper layers of the skin and can arise from various causes.
Acquired angioedema, or AAE, is a type of angioedema driven by a deficiency in a protein called C1-inhibitor (C1-INH). Besides regulating the activation of the immune system’s complement cascade, C1-INH also regulates the production of a signaling molecule called bradykinin. When C1-INH levels are low, bradykinin levels can rise too high, resulting in swelling.
AAE is often associated with lymphoproliferative disorders, most commonly non-Hodgkin lymphoma, a type of blood cancer. These disorders are marked by the uncontrolled proliferation of white blood cells.
In this study, researchers at Mayo Clinic in the U.S. described the case of a 45-year-old woman who had frequent angioedema attacks triggered by an underlying — yet undiagnosed — non-Hodgkin lymphoma, known as EMZL.
The patient presented to the clinic after experiencing recurrent abdominal pain, bloating, and distension for three years. Despite multiple consultations with gastrointestinal specialists in Panama, her home country, and extensive testing that included blood tests, imaging, and a small, noninvasive surgery, she received no specific diagnosis. Her liver enzymes were found to be elevated, however.
A year before her diagnosis, she started experiencing episodes of pain and swelling in her neck, shoulders, feet, and both hands, primarily in the knuckle. This was accompanied by joint stiffness. She denied having any rash, hives, or itching. This prompted a series of evaluations by several specialists and yielded a weakly positive signal in a test for rheumatoid factor, which is indicative of a potential autoimmune disorder called rheumatoid arthritis.
She received treatment with steroids, but improvements were temporary, prompting further evaluation by immunology specialists. Additional tests revealed a reduction in the levels of complement proteins, suggesting the possibility of AAE.
Blood work reveals signs of lymphoma
Due to limited access to specific treatments in her home country, she traveled to the U.S. At the Mayo Clinic, further blood tests confirmed mildly elevated rheumatoid factor and low levels of two complement proteins, namely C4 and C1q.
Importantly, C1-INH activity levels were also found to be low, at 21% (normal is 67% or higher). Overall, these lab findings confirmed the diagnosis of AAE due to C1-INH deficiency.
The potential link between AAE due to C1-INH deficiency and blood cancers prompted physicians to conduct further blood work. The results revealed signs of lymphoma, and imaging tests suggested possible involvement of the spleen, leading to a preliminary diagnosis of EMZL.
She started treatment with rituximab, an immunosuppressive therapy approved for certain cancers and autoimmune diseases, for four weeks. The treatment completely resolved her angioedema symptoms. C1q and C1-INH activity levels were normalized, and the spleen showed no lesions. A follow-up bone marrow biopsy indicated a reduction in lymphoma involvement to 10% of the marrow space.
The patient received another four doses of rituximab, administered every eight weeks. A follow-up bone marrow analysis showed no obvious signs of cancer cells.
Since treatment, the patient has remained symptom-free and is under surveillance, with laboratory checks every six months. By the time of the study’s publication, she had been followed for one year after completing the last round of rituximab.
Treatment of underlying conditions can ease angiodema symptoms
The researchers also conducted a literature review of published studies, including case reports, for common blood cancers associated with AAE due to C1-INH deficiency.
A total of 11 studies, involving 372 patients from Europe and the U.S., were analyzed. The most common condition associated with AAE due to C1-INH deficiency was non-Hodgkin lymphoma, with 141 diagnosed patients (38.2%). Of these, splenic marginal zone lymphoma was found in 15.6% of the cases.
Monoclonal gammopathy of undetermined significance, a benign precursor condition for lymphomas and other cancers, was found in 27.7% of the cases. Autoimmune disorders, including rheumatoid arthritis and Sjögren’s disease, were found in 9.1% of the cases. In 15.1% no underlying disorders were identified, highlighting AAE’s “complex nature and the requirement for additional research into its [mechanisms].”
According to experts, all patients — even those who lack underlying conditions — should undergo annual examinations for potential lymphoproliferative disorders.
Cases in the literature also indicate that patients can see their angioedema symptoms ease following treatment of underlying conditions, particularly lymphomas. Rituximab was highlighted as a commonly used agent in treating these disorders.
Overall, this case highlights the challenges of diagnosing AAE, which “requires specialized testing of [complement] and … early referrals to an immunologist,” the researchers wrote, adding that “suspicion for lymphoproliferative disorders should be high.” Comprehensive tests, including blood work, bone marrow analyses, and imaging tests, are warranted to identify underlying conditions.
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