Primary breast follicular lymphoma without a BCL2 rearrangement: insights into extranodal lymphoma biology

BACKGROUND: Primary breast lymphoma is a rare malignancy that accounts for less than 1% of non-Hodgkin lymphomas. Diffuse large B-cell lymphoma is the most common subtype, whereas follicular lymphoma (FL) accounts for only a small proportion of cases. Most FL cases involving the breast represent secondary involvement by systemic disease, and true primary breast FL is uncommon. Molecular characterization of primary breast FL has rarely been reported, and its genetic landscape remains poorly understood. CASE PRESENTATION: We report a case of primary breast FL, grade 3A, in a 55-year-old woman who presented with a palpable breast mass. Core needle biopsy revealed an atypical follicular lymphoid proliferation composed of centrocytes and numerous centroblasts (> 15 cells/high-power field). Immunohistochemistry revealed positivity for CD20, PAX5, CD10, and BCL6, with weak BCL2 expression, and a Ki-67 proliferation index of approximately 30%. Fluorescence in situ hybridization did not detect IGH::BCL2, BCL6, or MYC rearrangements but demonstrated copy-number gains involving BCL2, BCL6, MYC, and IGH. Next-generation sequencing identified biallelic CREBBP mutations and a FOXO1 mutation. Clonality studies confirmed a clonal IGK rearrangement in the breast lesion. Staging work-up with positron emission tomography/computed tomography showed disease confined to the breast (stage IE). The patient was treated with R-CHOP chemotherapy followed by involved-site radiotherapy. CONCLUSION: Our findings support the existence of a subset of extranodal follicular lymphomas lacking an IGH::BCL2 rearrangement and highlight alternative pathways of lymphomagenesis with implications for classification and diagnosis. The identification of biallelic CREBBP mutations and a FOXO1 mutation provides molecular insight into extranodal FL biology, suggesting an overlap with nodal FL while supporting alternative oncogenic pathways in extranodal disease.