The Mutation Is Not Necessarily the Lymphoma: Tumour-Infiltrating Clonal Haematopoiesis, Shared Clonal Ancestry and Cellular Attribution in Lymphoid Tissue Sequencing

Molecular sequencing has refined lymphoma classification while exposing a fundamental interpretative limitation: a mutation detected in lymphoid tissue cannot necessarily be attributed to the malignant clone. Clonal haematopoiesis may contribute genetically altered infiltrating cells, establish ancestral mutations shared by malignant and non-malignant lineages, or coexist independently with lymphoma. These relationships create two opposing attribution errors: assigning a non-malignant variant to the lymphoma and excluding a genuinely ancestral lymphoma-associated alteration because it is also detectable in blood. Recent investigations substantiate both biological possibilities, although their prevalence and diagnostic consequences in routine practice remain uncertain. This critical narrative review examines the evidentiary boundaries separating variant detection, cellular localisation, clonal ancestry, pathogenic involvement and clinical utility. Particular attention is given to compartment-resolved sequencing, molecular clonality, precursor-like lymphoid proliferations and emerging prognostic associations. A claim-specific framework of evidentiary sufficiency is proposed to distinguish conclusions supported by existing methods from those requiring further validation, with additional investigation reserved for potentially consequential diagnostic uncertainty. The central contention is that detecting an alteration establishes its presence, whereas attributing it to lymphoma requires independent evidence of cellular ownership and biological significance.