From Autoinflammation to Oncogenesis: A 17-Year Evolution of Schnitzler Syndrome with Marginal Zone Lymphoma, Injection-Site Amyloidosis, and Metastatic Melanoma

Schnitzler syndrome (SchS) is a rare, IL-1–mediated autoinflammatory disorder characterized by chronic urticaria, monoclonal gammopathy, and systemic inflammation. While hematologic transformation is recognized, long-term data on clonal evolution and solid tumor associations remain limited.

A 67-year-old man initially presented in 2006 with fatigue, night sweats, intermittent fevers, urticarial rash, and unintentional weight loss. Imaging revealed bilateral axillary and inguinal lymphadenopathy. Laboratory workup showed leukocytosis, thrombocytosis, anemia, and a small IgMκ monoclonal paraprotein. Bone marrow biopsy demonstrated hypercellularity with a B-cell infiltrate and kappa-restricted plasma cells, consistent with marginal zone lymphoma (MZL) with plasmacytic features. He was treated with R-CVP chemotherapy, achieving complete metabolic remission.

Despite hematologic response, systemic symptoms persisted. Infectious and autoimmune evaluations were unrevealing. Months later, the constellation of chronic urticaria, monoclonal gammopathy, and systemic inflammation raised suspicion for Schnitzler syndrome (SchS). He met diagnostic criteria and was started on daily subcutaneous anakinra, resulting in rapid and sustained symptom control for over a decade.

In 2023, the patient developed pancytopenia. Bone marrow biopsy revealed recurrent MZL involving 60–70% of the marrow. Flow cytometry confirmed aberrant B cells and kappa-restricted plasma cells. NGS identified MYD88 and CXCR4 mutations, along with TET2 and IGLL5 variants, and del(20q) on cytogenetics. He received four weekly doses of rituximab with hematologic improvement.

During restaging, a PET-avid cerebellar lesion was discovered. Surgical resection confirmed metastatic melanoma. He underwent stereotactic radiosurgery followed by dual checkpoint inhibition (ipilimumab and nivolumab), with no recurrence to date.

In early 2024, a firm nodule developed at the anakinra injection site. Biopsy revealed localized kappa-restricted amyloid deposits. Mass spectrometry confirmed AIL1RAP-type amyloidosis, a rare localized variant associated with chronic IL-1 blockade. No systemic amyloidosis was detected. Therapy was continued with site rotation.

As of mid-2025, the patient remains in remission from MZL and melanoma, with well-controlled SchS and stable localized amyloidosis.

This case underscores the intersection of autoinflammation, clonal hematopoiesis, iatrogenic amyloid deposition, and oncologic transformation. It highlights the importance of genomic surveillance in SchS and long-term safety considerations with IL-1 inhibition.