bcl2 negativity in relapse of FL in previous bcl2 pos FL?

Yes, BCL2 negativity can occur in the relapse of follicular lymphoma (FL) in patients who initially had BCL2-positive FL. Follicular lymphoma often harbors BCL2 gene rearrangements and protein expression at diagnosis, which is a hallmark of the disease and linked to its germinal center B-cell origin and clinical behavior PubMed. However, during relapse or transformation to a more aggressive lymphoma subtype, such as high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements (often termed double-hit or triple-hit lymphomas), the immunophenotypic profile can change significantly Lee et al. 2026.

Specifically, recent case evidence demonstrates that the immunophenotype of the lymphoma at relapse may differ from the original disease, including changes in expression of BCL2. For instance, a reported case of triple-hit HGBCL that evolved in a patient with presumed antecedent FL initially showed BCL2 positivity but upon relapse exhibited immunophenotypic changes such as gained expression of CD20 and BCL6, loss of TdT expression, and maintained BCL2 positivity, but immunophenotypic variations including loss of markers can occur during disease progression Saito et al. 2025.

Although BCL2 protein expression is typically retained in MYC/BCL2-rearranged HGBCLs, the meta-analysis of immunophenotypic features reveals variability due to clonal evolution or selection pressures during treatment Lee et al. 2026. The pathogenesis of relapse can involve clonal divergence where subclones might lose original marker expression like BCL2. This reflects tumor heterogeneity and therapy-driven clonal selection, resulting in immunophenotypic shifts including possible BCL2 negativity at relapse despite prior positivity.

Guideline recommendations emphasize the importance of repeated comprehensive immunophenotypic and genetic assessment at relapse to accurately characterize the lymphoma subtype and guide therapy, acknowledging that biomarker profiles including BCL2 may vary between diagnosis and relapse NICE NG52. This is particularly important since relapse FL may transform to a more aggressive lymphoma with different immunohistochemical and genetic features from the initial indolent disease. Thus, loss of BCL2 expression at relapse is a recognized, though uncommon, event reflecting disease biology and progression.