The Involvement of PI3K-Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease-Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes
04/22/2025 Important insight for Castleman disease patients: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder that is clinically classified into three subtypes: idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). The authors clarify the histopathological characteristics of each clinical subtype across 37 patients and perform a whole-transcriptome analysis focusing on angiogenesis-related gene expression. These results suggest that the PI3K-Akt pathway plays an important role in the pathogenesis of TAFRO/NOS subtypes of iMCD.
Summary: This open-access research article investigates why the clinical subtypes of idiopathic multicentric Castleman disease (iMCD) look and behave so differently at the tissue level, focusing on blood-vessel formation (angiogenesis) and its molecular drivers. iMCD is classified into three subtypes—idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS)—which show differing degrees of vascularity, though the underlying mechanisms have been poorly understood. Examining lymph-node histopathology in 37 patients and performing whole-transcriptome (gene-expression) analysis focused on angiogenesis-related genes, the authors found that the TAFRO and NOS subtypes had significantly more vascularization than IPL, with more atrophic germinal centers, characteristic “whirlpool vessels,” and more endothelial cells in interfollicular areas. Gene-expression analysis showed the PI3K–Akt signaling pathway was significantly enriched in the TAFRO/NOS groups; because this pathway—potentially activated by vascular endothelial growth factor A (VEGF-A) and certain integrins—increases vascular permeability, it may explain the anasarca and fluid retention seen in those subtypes. The authors conclude that PI3K–Akt signaling plays an important role in the pathogenesis of TAFRO/NOS, pointing to a possible mechanism-based distinction (and potential therapeutic target) among iMCD subtypes.