Post-transplant lymphoproliferative disorders (PTLD) and lymphomas in immunocompromised individuals represent significant clinical challenges, with a limited understanding of their pathogenesis. We investigated a PTLD cohort (n = 50) consisting of 'early lesions' (infectious mononucleosis-like PTLD, plasmacytic and follicular hyperplasias), polymorphic PTLD and post-transplant diffuse large B-cell lymphomas (PT-DLBCL). The study also included 15 DLBCL with autoimmune/immunocompromised backgrounds (IS-DLBCL) and 14 DLBCL, not otherwise specified (DLBCL, NOS), as control. To investigate microarchitectural and genetic changes, immunohistochemistry, multiplex immunofluorescence (mIF), fluorescence in situ hybridisation and high-throughput sequencing were performed. Scarcity of viral infections other than Epstein-Barr virus (EBV) was observed. mIF revealed lower Treg infiltration in PT-DLBCL and high CD8