From G tolerance to physiological state monitoring: mechanisms and adaptive protection.

Intravascular large B‐cell lymphoma (IVLBCL) is a rare B‐cell neoplasm that is restricted to intravascular growth pattern (particularly small‐sized vessels) []. It classically presents as widespread disease in extranodal sites, with a preponderance for the bone marrow, but other organs can be affected []. Nodal involvement is not usually seen. It is an extremely uncommon type of lymphoma affecting both genders with a slight male predominance. It has an age‐adjusted incidence rate of around 0.095 cases per 1,000,000 individuals in the United States, with an increasing incidence over time []. There are three types of IVLBCL described in the literature. The classical subtype is predominantly observed in Western countries and mainly presents with nonspecific symptoms such as fever of unknown origin, central nervous system involvement, and skin manifestations; it was formerly designated as the Western variant. The classical subtype may also involve other organs, leading to a wide range of clinical presentations [, ]. The second subtype is the one associated with hemophagocytic lymphohistiocytosis (HLH) which was formerly designated as the Asian variant, and it is characterized by pancytopenia, hepatosplenomegaly, and systemic inflammation. This form of IVLBCL usually lacks neurological abnormalities and skin manifestations []. There is a third variant which is the one confined to the skin compatible with primary cutaneous IVLBCL. It has a better prognosis compared to the classic and HLH variants. The pathogenesis of IVLBCL‐induced HLH is orchestrated by an excessive immune response. The neoplastic B‐cells can trigger a hyperinflammatory state by producing high levels of cytokines such as interferon‐gamma (IFN‐γ), tumor necrosis factor‐alpha (TNF‐α), and interleukin‐6 (IL‐6). These cytokines activate macrophages and cytotoxic T‐cells, leading to hemophagocytosis, where activated macrophages ingest hematopoietic cells, such as red blood cells [, ]. In addition, genetic mutations involving the NF‐κB signaling pathway and immune checkpoint regulators contribute to immune escape and persistent activation of the immune system. Mutations in genes like MYD88 and CD79B are frequently observed and are associated with the activation of proinflammatory pathways []. The clinical course of the disease is aggressive, with a 5‐year overall survival (OS) rate ranging from 46.3% to 52%. Poor prognostic factors include, but are not limited to, old age, nodal involvement, bone marrow involvement, high International Prognostic Index (IPI) scores, and treatment regimen (lack of anthracycline‐based chemotherapy and treatment without rituximab are associated with worse outcomes) [, ].