PCNSL are rare aggressive tumors characterized by a distinct clinical feature. The diagnostic and molecular features of these lymphomas will be presented.

Traditionally, immunodeficiency-associated lymphoproliferations (LPDs) have been classified according to their immunodeficiency background (e.g. HIV, post-solid-organ transplantation, MTX). Newly recognized immune deficiency settings, and increasingly immune dysregulations (IDD), as well as recognition of the broader histopathological spectrum of these disorders have necessitated a novel and critical approach.
Multi-chemotherapy cancer treatment including the rapidly expanding field of immune modulatory treatments (checkpoint inhibitors, antibody treatment and others) and CAR-T approaches are now emerging as a novel IDD settings. Case reports and small series on associated B- and T-LPDs have been reported.
The oncogenetic and immunological mechanisms underlying the risk for secondary LPDs after cancer treatment are most probably various. Chemotherapy-associated LPDs primarily stem from severe, prolonged general iatrogenic T-cell lymphopenia, which impairs regular immune surveillance and permits the opportunistic reactivation of oncogenic viruses—most notably EBV. Published series suggest primarily a risk for EBV+ B-LPDs that cover the complete spectrum from hyperplasias to overt lymphomas, reminiscent of those seen in classic IDD settings such as PTLD. Direct cytotoxicity of chemotherapy and radiotherapy may target emerging lymphoid proliferation, but in contrast to secondary solid malignancies likely play a limited role in oncogenic risk.
Immunotherapy-mediated LPDs arise from a more specific disruptive reset of immune homeostasis that rather leads to autoimmune and auto-inflammatory dysregulation, including hyper-inflammatory states and unchecked lymphoid proliferation rather than viral escape. The resulting LPDs are rarely EBV-associated. The histopathological spectrum of immunotherapy-induced LPDs, as far as we know now, seems to be more complex. These often manifest with atypical granulomatous features, prominent T-cell infiltration, and exuberant histiocytic reactions, frequently mimicking sarcoidosis and when presenting in the digestive tract as enteropathies. Differentiation from infectious complications can be difficult.
Differential diagnostic decisions are challenging and require in depth morphological immunological and molecular evaluation. Simple statements on "reactive expansion” and “true malignancy” does not do justice to our biological understanding. Rather, multidisciplinary tumor board discussion are essential to interpret the pathology findings in the clinical context in light of the understanding of their underlying biology and decide on their clinical consequences, avoiding unnecessary cytotoxic treatment and considering novel targeted immune-modulating or viral-directed therapies.