Sato, Yasuharu

ABSTRACTIdiopathic 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.

AimsKikuchi‐Fujimoto disease (KFD) is a rare disease that typically manifests with fever and cervical lymphadenopathy. Little is known about the risk factors associated with recurrence and their correlation with clinicopathologic features.Methods and ResultsWe analysed 112 patients with KFD, predominantly female (61/112, 54.5%), with an average age of 29.4 years. The incidence was higher in males up to the age of 20 and higher in females from their 30s onwards. Of the 70 patients with follow‐up data, 23% experienced recurrence. Recurrence was associated with lower C4 levels (P = 0.038) and higher antinuclear antibody (ANA) rates (P = 0.007) compared to transient disease. The mean duration of symptoms was 71.5 days. Lymph node histology in 98 cases (excluding 14 needle biopsy specimens) was classified into three patterns: proliferative (n = 75, 77%), necrotizing (n = 22, 22%), and xanthomatous (n = 1, 1%). The necrotizing pattern associated with significantly enlarged lymph nodes (P = 0.047) and a longer symptom duration (P = 0.009) than the proliferating pattern. The number of CD4‐positive lymphocytes was significantly lower in the necrotizing type than in the proliferative type (P < 0.001).ConclusionThese results indicated that low C4 levels and positive ANA were associated with KFD recurrence. Although the aetiology of KFD remains elusive, given that some cases develop autoimmune disease, the results suggest that patients with recurrent KFD represent an intermediate status between those with transient KFD and those with overt autoimmune disease. The comprehensive clinicopathological findings of this study may be useful for elucidating its pathogenesis and predicting the clinical course.

Introduction: Hyaline-vascular type unicentric Castleman disease (HV-UCD) is a classic variant of Castleman disease, characterized by localized lymph node hyperplasia. Due to its rarity, there have been few systematic reports summarizing its clinicopathological features globally. Also, its pathogenesis remains unelucidated. The present study aims to provide a detailed clinicopathological and transcriptomic analysis of HV-UCD to enhance the understanding of its underlying mechanisms at a molecular level. Methods: We conducted a clinicopathological analysis of 51 HV-UCD cases and performed whole transcriptome analysis on frozen lymph node specimens from four cases. Differentially expressed genes (DEGs) and Gene Ontology (GO) analyses were performed to identify significant pathways and biological processes involved in HV-UCD, with reactive lymphoid hyperplasia as control. Results: The mean age of HV-UCD patients was 42.8 years, with no significant gender differences. The most common sites involved were the abdominal cavity (n = 18, 35.3%), mediastinum (n = 11, 21.6%), and retroperitoneum (n = 9, 17.6%), with an average size of the lesions being 4.8 cm. Histologically, 33.3% of cases exhibited “dysplastic follicular dendritic cells (dFDCs)” characterized by multinucleation or large nuclei within and outside follicles, positive for follicular dendritic cells (FDC) markers. DEGs analysis compared to reactive lymphoid hyperplasia revealed significant upregulation of genes related to FDCs and angiogenesis. Notably, the placental growth factor (PGF), a proangiogenic factor and a member of the VEGF family, demonstrated significant overexpression. GO analysis identified significant enrichment of genes involved in angiogenesis, cell adhesion, tissue architecture, and humoral immunity. Discussion: This large cohort of HV-UCD cohort provides potentially novel clinicopathological insights. Gene expression analysis demonstrated increased expression of FDC-related genes, suggesting a pivotal role of FDCs in HV-UCD pathogenesis. The differences in the gene profiles related to angiogenesis may contribute to the distinct mechanisms and histological features of HV-UCD and iMCD-TAFRO, where HV-UCD is associated with hyalinization of vascular walls and iMCD-TAFRO is characterized by angiogenesis with endothelial cell swelling. Conclusion: The present results suggest the crucial role of FDCs in HV-UCD pathogenesis from the molecular features. Currently, there are no objective diagnostic markers for HV-UCD. Identifying these markers may lead to a clearer understanding of the disease pathophysiology and improve diagnostic accuracy for HV-UCD. Further investigation is warranted to verify the findings.

Introduction: Kikuchi-Fujimoto disease (KFD), is a rare inflammatory disease of unknown etiology, typically presenting with transient fever and cervical lymphadenopathy. It is recently classified as a tumor-like lesion in the World Health Organization Classification 5th Edition. There are few large-scale studies on patient demographics and clinical course. This study aims to report detailed clinicopathological features of KFD. Methods: We reviewed 112 cases of KFD diagnosed at Okayama University Department of Pathology and Oncology, Okayama, Japan between 2012 and 2022. Patients who were diagnosed with autoimmune diseases or bacterial/tuberculous lymphadenitis after the initial presentation as KFD were excluded. Results: The average age of the included cases was 29.4 years (range:6 to 77 years) with slight female predominance (n = 51/115, 44.3% for male; n = 61/115, 53.0% for female). For the included cases of 30 years or older, there were more females than males. The cervical lymph nodes were the most commonly affected sites (85%). For the 70 patients who had complete follow-up data available in the electric medical records, the recurrence rate was 23%, without a difference between males and females. Laboratory tests demonstrated significantly lower complement 4 (C4) levels (p = 0.038) and a higher rate of positive antinuclear antibodies (p = 0.007) in the relapsed cases than in the cases without documented recurrence. The mean number of days prior to confirm the diagnosis was 71.5 days. Among the representative lymph node histology classification, proliferative type was the most common (n = 75; 77%), followed by necrotizing (n = 22; 22%), and xanthomatous (n = 1; 1%). The patients with necrotizing type had significantly enlarged lymph nodes (p = 0.047) and longer duration of symptoms (p = 0.009) compared to the proliferating type. Discussion: The present study provides data from a large KFD cohort to provide comprehensive clinicopathological information to date. While KFD is known to predominantly affect female, there were considerably more males up to age 30 than females, Being young and adolescent male KFD patients was associated with atypical features. Future studies are warranted to confirm the findings noted in the results, to clarify clinicopathological differences in the male young adolescent KFD, and further characterize the classical female KFD cases, including histological features, treatment responses, and association with autoimmune or malignant hematology conditions. Conclusion: In this study, we analyzed a large number of KFD cases and clarified characteristics. The comprehensive clinicopathological features provided by the present results may be useful in elucidating the pathogenesis and predicting the clinical course of such clinically challenging cases, including association with autoimmune diseases and its long-term outcomes.

AbstractIdiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or “mixed.” Though the etiology is unknown, a pro‐inflammatory cytokine storm, often involving interleukin‐6 (IL‐6), contributes to pathogenesis. Anti‐IL‐6 therapy with siltuximab is the only FDA‐ or EMA‐approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first‐line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real‐world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real‐world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.

Abstract Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.