Citations

Abstract Introduction: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by systemic inflammation of unknown etiology. Clinically, iMCD is classified into idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly (TAFRO), and not otherwise specified (NOS) subtypes. Among these, TAFRO and a subset of NOS cases share overlapping clinicopathological features and often follow a fatal clinical course. However, the pathogenesis remains largely undefined. This study combines a comprehensive transcriptomic analysis with histological assessment, focusing on vascular proliferation to elucidate the molecular mechanisms of the TAFRO subtype. Methods: We conducted a pathological analysis of nine IPL, nine TAFRO, and eight NOS cases, and performed transcriptome analysis from frozen lymph node specimens from 12, two, and four IPL, TAFRO, and NOS cases, respectively. Differentially expressed genes (DEGs) and KEGG pathway analysis were performed to identify significant pathways in TAFRO and NOS, with IPL cases as controls. Results: Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO: p < 0.001, IPL vs NOS: p = 0.002). In addition, “whirlpool vessels” in GCs were seen in most cases in TAFRO and NOS (TAFRO: 9/9, 100%, NOS: 6/8, 75%), but not in IPL (IPL vs TAFRO: p < 0.001, IPL vs NOS: p = 0.007). Immunostaining for Ets-related gene revealed that the number of endothelial cells of TAFRO and NOS was significantly larger than that in IPL (TAFRO vs IPL: p < 0.001, NOS vs IPL: p = 0.002). KEGG pathway analysis revealed the PI3K–Akt signaling pathway was significantly enriched in the TAFRO/NOS groups. Immunohistochemistry of phosphorylated Akt and phosphorylated p38, both upstream and downstream effectors of the PI3K–Akt signaling pathway, were positive in vascular endothelial cells of TAFRO and NOS. Discussion: TAFRO and NOS exhibit marked angiogenesis and are histologically distinct from IPL. Furthermore, this angiogenesis is thought to be driven by upregulation of the PI3K–Akt signaling pathway, which may also contribute to extravascular fluid leakage, potentially leading to pleural and ascitic effusion or systemic edema observed in the TAFRO subtype. Conclusion: The present results suggest the crucial role of PI3K–Akt signaling pathway in TAFRO pathogenesis from transcriptomic and histopathological findings. This mechanistic insight may help elucidate the distinct pathogenesis of iMCD subtypes.

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.

Abstract Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8–negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm–driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have “oligocentric” lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.

Abstract Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

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.

AbstractCastleman disease (CD) describes a group of at least 4 disorders that share a spectrum of characteristic histopathological features but have a wide range of etiologies, presentations, treatments, and outcomes. CD includes unicentric CD (UCD) and multicentric CD (MCD), the latter of which is divided into idiopathic MCD (iMCD), human herpes virus-8 (HHV8)-associated MCD (HHV8-MCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS)-associated MCD (POEMS-MCD). iMCD can be further subclassified into iMCD–thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD–not otherwise specified (iMCD-NOS). Advances in diagnosis, classification, pathogenesis, and therapy are substantial since the original description of UCD by Benjamin Castleman in 1954. The advent of effective retroviral therapy and use of rituximab in HHV8-MCD have improved outcomes in HHV8-MCD. Anti–interleukin-6–directed therapies are highly effective in many iMCD patients, but additional therapies are required for refractory cases. Much of the recent progress has been coordinated by the Castleman Disease Collaborative Network (CDCN), and further progress will be made by continued engagement of physicians, scientists, and patients. Progress can also be facilitated by encouraging patients to self-enroll in the CDCN’s ACCELERATE natural history registry (#NCT02817997; www.CDCN.org/ACCELERATE).

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.

Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples. The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.