ASH 2024 | Advancing the diagnosis of Castleman disease by analyzing stromal cells in lymph nodes

My work tackles this first problem that Castleman disease patients face, which is getting a correct and prompt diagnosis. Right now, we have one of the largest registries of Castleman disease patients worldwide here at the Castleman Disease Collaborative Network in Philadelphia, and we routinely encounter situations where hematopathologists, the people who are essential for rendering the diagnosis of Castleman disease based on histopathologic review of the lymph node biopsy, disagree to the extent the changes can be called Castleman, to the fact that a number of different collection of nonspecific histologic findings have to be present to a certain degree to reach a Castleman disease diagnosis. Given discordance in pathologic interpretation, disagreements about whether or not a sample is Castleman disease or not, and the reflective differing abilities and experience that pathologists have in reaching a correct and prompt diagnosis of Castleman disease. My work aims to make that diagnosis easier. What I looked at was the stromal cells. Most of the lymph node is made of white blood cells, hematopoietic cells. I looked at cells that are non-hematopoietic mesenchymal fibroblasts endothelial cells that play a role traditionally in the structure of the lymph node, setting off different rooms and sections of the lymph node for the humoral or cell-mediated immune response. My work shows that these cells aren’t simply playing a structural role, but may play a more immunologic role, controlling, providing air traffic control signals to the immune system, into the white blood cells that create the systemic inflammatory disease that’s characteristic of Castleman. Specifically, I showed that one kind of these fibroblasts, these myofibroblasts, are much more differentially expanded compared to more T-zone fibroblastic reticular cells in unicentric Castleman disease. This is something we noticed by single-cell RNA sequencing compared to otherwise inflamed lymph nodes that were not Castleman disease. So a very high standard of inflammatory control. And we still see what’s specific for Castleman inflammation is this prevalence of the myofibroblast. And this was present when we did single cell RNA sequencing. We can also see this on using spatial transcriptomics as a way of orthogonal validation. And altogether, what I hope this will lead to is the development of immunohistochemical stains that can be more widely used by more community and diverse hematopathologists to allow them to better make a Castleman diagnosis so the patients can get their diagnosis more promptly and more correctly.

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