Paraneoplastic Syndrome of Angiomatoid Fibrous Histiocytoma May Be Caused by EWSR1-CREB1 Fusion-induced Excessive Interleukin-6 Production

Abstract

We describe a 7-year-old girl with angiomatoid fibrous histiocytoma (AFH) presenting severe inflammatory symptoms. The cytokine/chemokine profile of serum samples before and after surgery demonstrated that interleukin (IL)-6 had decreased by the greatest percentage. The AFH cells were immunopathologically positive for IL-6 and Tyr705-phosphorylation of signal transducer and activator of transcription 3. The EWSR1-CREB1 fusion gene detected in the tumor leads to continuous activation of CREB1 and IL-6 production, because the promoter region of IL-6 has a CREB binding site. Thus, IL-6 plays pivotal roles in both paraneoplastic syndrome and the oncogenesis of AFH.

Therapeutic response of metastatic angiomatoid fibrous histiocytoma carrying EWSR1‐CREB1 fusion to the interleukin‐6 receptor antibody tocilizumab

“…The pathogenesis of tumoral cytokine production as a result of EWSR1‐CREB1 fusion is thought to be related to the nature of the chimeric protein. The EWSR1 protein is a member of the TET family (whose members contain characteristic COOH‐terminal RNA‐binding domains) that likely acts as an adapter between transcription and RNA processing . The CREB1 protein is a transcription factor that plays a role in the regulation of cell differentiation, proliferation, and survival .…”

“…The CREB1 protein is a transcription factor that plays a role in the regulation of cell differentiation, proliferation, and survival . The EWSR1‐CREB1 fusion gene results in continuous activation of CREB1 motifs which upregulate IL‐6 production . It has been postulated that IL‐6 in AFH may function as an autocrine growth factor, as observed in other malignancies such as prostate cancer and multiple myeloma .…”

“…Additionally, the child had a number of adverse effects from the chemotherapy, including bone marrow suppression that, in combination with his underlying illness, resulted in 10 transfusions of packed red blood cells. During this time, we became aware of two cases of IL‐6 secretion associated with AFH—one involving a pediatric patient with EWSR1‐CREB1 fusion with paraneoplastic symptoms caused by IL‐6 production that resolved after tumor excision, and the other an adult patient with an unclassified malignancy associated with high IL‐6 production (subsequently classified as AFH) whose symptoms improved using tocilizumab, an IL‐6 inhibitor …”

“…At present, no available therapies are effective in targeting these EWSR1 and FUS fusions, and therefore we searched for alternative therapeutic strategies targeting vulnerabilities associated with this molecular alteration in AFH. Interleukin‐6 (IL‐6) secretion has been described in tumors with EWSR1‐CREB1 fusion and may promote tumor growth due to autocrine stimulation . Additionally, it has been suggested that increased IL‐6 may cause paraneoplastic syndrome characterized by fever, malaise, and anemia .…”

“…Interleukin-6 (IL-6) secretion has been described Abbreviations: AFH, angiomatoid fibrous histiocytoma; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hgb, hemoglobin; IL-6, interleukin 6; PET, positron emission tomography in tumors with EWSR1-CREB1 fusion and may promote tumor growth due to autocrine stimulation. 6,7 Additionally, it has been suggested that increased IL-6 may cause paraneoplastic syndrome characterized by fever, malaise, and anemia. 6,7 Tocilizumab is an IL-6 receptor antibody that has potential benefit as a targeted therapy in refractory neoplasms with IL-6 secretion.…”