B-Cell Lymphoma Following an Indolent Course Over 30 Years with Immunophenotypic Changes at Each Recurrence.

Introduction: Diffuse large B-cell lymphoma (DLBCL) comprises biologically distinct subtypes, but whether cell-of-origin-related features remain stable over long disease courses is unclear. Case description: A woman was initially diagnosed with CD20-positive B-cell lymphoma in 1988 and treated with cyclophosphamide, vincristine and prednisolone (COP) chemotherapy. She experienced a first relapse in 1998 and received cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy. The second relapse occurred in 2008 and was managed with rituximab. At the third relapse in 2011, rituximab plus bendamustine (RB) was administered. During the fourth relapse in 2015, R-pirarubicin (THP)-COP chemotherapy was given. At the fifth relapse in 2017, at 80 years of age, RB therapy was administered again. A sixth relapse occurred in 2019, and the patient died within the same year. Histopathological evaluation throughout the disease course consistently demonstrated DLBCL. Notably, the immunophenotype showed sequential changes from a germinal centre B-cell-like pattern to an activated B-cell-like pattern and ultimately to a CD30-positive anaplastic B-cell variant. Discussion: This unusually long clinical course highlights stepwise immunophenotypic evolution during repeated relapses, suggesting that surrogate subtype profiles may change over time. Conclusion: Repeat biopsies with comprehensive pathological (and, when available, molecular) re-evaluation are important to accurately characterize relapsed DLBCL and inform treatment selection. LEARNING POINTS: Diffuse large B-cell lymphoma (DLBCL) can undergo stepwise immunophenotypic and molecular evolution over decades, progressing from a germinal Center B-cell-like (GCB)-like phenotype to an activated B-cell -like/non-GCB pattern (MUM1+, CD30+) and ultimately to an aggressive anaplastic variant.The cell-of-origin profile and its associated molecular features are not necessarily static; thus, therapeutic strategies for relapsed DLBCL should be tailored to the current disease state rather than relying on the signature at initial diagnosis.Longitudinal re-evaluation through repeat biopsies is imperative to capture the evolving landscape of the malignancy, ensuring that treatment selection is guided by the most recent pathological and molecular findings.