International Consensus Histopathological Criteria for Subtyping Idiopathic Multicentric Castleman Disease Based on Machine Learning Analysis.

Journal: American journal of hematology
Published Date: Jun 20, 2025

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder classified into three recognized clinical subtypes-idiopathic plasmacytic lymphadenopathy (IPL), TAFRO, and NOS. Although clinical criteria are available for subtyping, diagnostically challenging cases with overlapping histopathological features highlight the need for an improved classification system integrating clinical and histopathological findings. We aimed to develop an objective histopathological subtyping system for iMCD that closely correlates with the clinical subtypes. Excisional lymph node specimens from 94 Japanese iMCD patients (54 IPL, 28 TAFRO, 12 NOS) were analyzed for five key histopathological parameters: germinal center (GC) status, plasmacytosis, vascularity, hemosiderin deposition, and "whirlpool" vessel formation in GC. Using hierarchical clustering, we visualized subgroups and developed a machine learning-based decision tree to differentiate the clinical subtypes and validated it in an external cohort of 12 patients with iMCD. Hierarchical cluster analysis separated the IPL and TAFRO cases into mutually exclusive clusters, whereas the NOS cases were interspersed between them. Decision tree modeling identified plasmacytosis, vascularity, and whirlpool vessel formation as key features distinguishing IPL from TAFRO, achieving 91% and 92% accuracy in the training and test sets, respectively. External validation correctly classified all IPL and TAFRO cases, confirming the reproducibility of the system. Our histopathological classification system closely aligns with the clinical subtypes, offering a more precise approach to iMCD subtyping. It may enhance diagnostic accuracy, guide clinical decision-making for predicting treatment response in challenging cases, and improve patient selection for future research. Further validation of its versatility and clinical utility is required.

Authors

  • Midori Filiz Nishimura
    Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
  • Tomoka Haratake
    Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
  • Yoshito Nishimura
    Division of Hematology/Oncology, Mayo Clinic, Rochester, Minnesota, USA.
  • Asami Nishikori
    Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
  • Remi Sumiyoshi
    The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group, Nagasaki, Japan.
  • Hideki Ujiie
    Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Ontario, Canada.
  • Yuri Kawahara
    Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
  • Tomohiro Koga
    The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group, Nagasaki, Japan.
  • Masao Ueki
    Tohoku Medical Megabank Organization (ToMMo), Tohoku University, Sendai, Miyagi, Japan.
  • Dorottya Laczko
    Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Eric Oksenhendler
    Department of Clinical Immunology, Hôpital Saint-Louis, Paris, France.
  • David C Fajgenbaum
    Center for Cytokine Storm Treatment and Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Frits van Rhee
    Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
  • Atsushi Kawakami
    The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group, Nagasaki, Japan.
  • Yasuharu Sato
    Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Okayama, Japan.

Keywords

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