Multicentric Castleman's Disease Research Articles

The value of a PET scan in selecting the best lymph node to biopsy, and confirming the diagnosis of idiopathic multicentric Castleman disease with HLH and EBV viremia in a previously healthy adult

Introduction: Castleman disease (CD) is a rare lymphoproliferative disorder having a variegated clinical presentation. Diagnosis of the idiopathic HIV- and HHV8-negative multicentric CD (iMCD) subtype poses a challenge given its non-specific clinical manifestations. iMCD presents as diffuse lymphadenopathy with inflammatory manifestations, primarily driven by interleukin-6 (IL-6). Treatment includes suppressing the inflammation by targeting IL-6 with monoclonal antibodies such as siltuximab and, in severe cases, immuno-chemotherapy to control B- and plasma-cell activation. Case description: A previously healthy 43-year-old male presented to the emergency department with fever, night sweats, anasarca, anaemia, thrombocytopenia and acute renal insufficiency. Extensive blood and imaging workup was initiated. Several diagnoses were entertained including viral infections (comprising COVID-19), haemophagocytic lymphohistiocytosis, lymphoma and autoimmune conditions. Initial axillary lymph node biopsy was not diagnostics. A positron emission tomography (PET) scan showed diffuse and symmetrical cervical and hilar/mediastinal lymphadenopathies. A mediastinal lymph node biopsy was then performed and indicated iMCD. The patient was treated with high-dose steroids and siltuximab. An Epstein-Barr virus (EBV) PCR was positive, and rituximab was added to the treatment. The patient recovered and felt well after two months. Conclusions: Non-specific symptoms, non-diagnostic first biopsy and iMCD resemblance to haemophagocytic lymphohistiocytosis further complicated the diagnosis. A PET scan allowed the best selection of a lymph node to be biopsied. Anti-IL6 is the recommended treatment; however, we are lacking information on the duration of siltuximab, and the long-term toxicity and immunosuppressive effect of this treatment. The contribution of EBV reactivation in the development and treatment of iMCD needs further investigation.

The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis

The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis

Rapid relapse of idiopathic multicentric Castleman disease after siltuximab discontinuation in a case with complete remission for more than 10 years.

Rapid relapse of idiopathic multicentric Castleman disease after siltuximab discontinuation in a case with complete remission for more than 10 years.

Unicentric Castleman Disease: Updates and Novel Insights Into Spindle Cell Proliferations and Aggressive Forms of a Localized Disease.

Castleman Disease (CD) is a rare lymphoproliferative disorder that can be separated into two primary forms: Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). UCD is localized, while MCD is systemic. Though UCD generally has a favorable prognosis following surgical resection, more aggressive forms of this disease have been identified, including cases associated with dendritic and spindle cell proliferation. Genetic analysis has deepened our understanding of UCD. Despite advancements in better understanding the pathophysiology of UCD, challenges persist in the diagnosis, management, and treatment due to its rarity and heterogeneity. Here, we review current knowledge on UCD, highlighting the epidemiology, clinical presentation, diagnostic criteria, and treatment options while emphasizing the need for further research and innovation in therapeutic strategies.

TAFRO subtype of idiopathic multicentric Castleman disease in a 22-year-old man.

TAFRO subtype of idiopathic multicentric Castleman disease in a 22-year-old man.

Molecular Mechanisms of Kaposi Sarcoma-Associated Herpesvirus (HHV8)-Related Lymphomagenesis

Approximately 15–20% of cancers are caused by viruses. Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is an oncogenic virus that is the etiologic agent of not only Kaposi sarcoma but also the lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV can infect a broad tropism of cells, including B lymphocytes, wherein KSHV encodes specific viral proteins that can transform the cell. KSHV infection precedes the progression of PEL and MCD. KSHV establishes lifelong infection and has two phases of its lifecycle: latent and lytic. During the latent phase, viral genomes are maintained episomally with limited gene expression. Upon sporadic reactivation, the virus enters its replicative lytic phase to produce infectious virions. KSHV relies on its viral products to modulate host factors to evade immune detection or to co-opt their function for KSHV persistence. These manipulations dysregulate normal cell pathways to ensure cell survival and inhibit antiviral immune responses, which in turn, contribute to KSHV-associated malignancies. Here, we highlight the known molecular mechanisms of KSHV that promote lymphomagenesis and how these findings identify potential therapeutic targets for KSHV-associated lymphomas.

Development of KSHV vaccine platforms and chimeric MHV68-K-K8.1 glycoprotein for evaluating the in vivo immunogenicity and efficacy of KSHV vaccine candidates.

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 is an etiological agent of Kaposi's Sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Considering the high seroprevalence reaching up to 80% in sub-Saharan Africa, an effective vaccine is crucial for preventing KSHV infection. However, vaccine development has been limited due to the lack of an effective animal model that supports KSHV infection. Murine Herpesvirus 68 (MHV68), a natural mouse pathogen persisting lifelong post-infection, presents a promising model for KSHV infection. In this study, we developed KSHV vaccine and a chimeric MHV68 carrying the KSHV glycoprotein, serving as a surrogate challenge virus for testing KSHV vaccines in a mouse model. Among KSHV virion glycoproteins, K8.1 is the most abundant envelope glycoprotein with the highest immunogenicity. We developed two K8.1 vaccines: K8.1 mRNA-lipid nanoparticle (LNP) vaccine and K8.126-87-Ferritin (FT) nanoparticle vaccines. Both induced humoral responses in immunized mice, whereas K8.1 mRNA LNP also induced T cell responses. Using BACmid-mediated homologous recombination, the MHV68 M7 (gp150) gene was replaced with KSHV K8.1 gene to generate chimeric MHV68-K-K8.1. MHV68-K-K8.1 established acute and latent infection in the lungs and spleens of infected mice, respectively. Mice immunized with K8.1 mRNA LNP or K8.126-87-FT showed a reduction of MHV68-K-K8.1 titer but not MHV68 wild type (WT) titer in the lung. In addition, viral reactivation of MHV68-K-K8.1 was also significantly reduced in K8.1 mRNA LNP-immunized mice. This study demonstrates the effectiveness of two vaccine candidates in providing immunity against KSHV K8.1 and introduces a surrogate MHV68 system for evaluating vaccine efficacy in vivo.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is a prevalent virus that establishes lifelong persistent infection in humans and is linked to several malignancies. While antiretroviral therapy has reduced Kaposi's Sarcoma (KS) complications in people with HIV, KS still affects individuals with well-controlled HIV, older men without HIV, and transplant recipients. Despite its significant impact on human health, however, research on KSHV vaccine has been limited, mainly due to the lack of interest and the absence of a suitable animal model. This study addresses these challenges by developing KSHV K8.1 vaccine with two platforms, mRNA lipid nanoparticle (LNP) and FT nanoparticle. Additionally, chimeric virus, MHV68-K-K8.1, was created to evaluate KSHV vaccine efficacy in vivo. Vaccination of K8.1 mRNA LNP or K8.126-87-FT significantly reduced MHV68-K-K8.1 titers. Developing an effective KSHV vaccine requires an innovative approach to ensure safety and efficacy, especially for the immunocompromised population and people with limited healthcare resources. This study could be a potential blueprint for future KSHV vaccine development.

Interleukin‐6 transcripts up‐regulation in lymph nodes from unicentric and multicentric Castleman disease

AbstractIntroductionCastleman disease (CD) represents a spectrum of heterogeneous lymphoproliferative disorders sharing peculiar histopathological features, clinically subdivided into unicentric CD (UCD) and multicentric CD (MCD) and presenting with variable inflammatory symptoms. Interleukin (IL)‐6 and other cytokines play a major role in mediating CD inflammatory manifestations. Although the local microenvironment seems to be among the major sources of hypercytokinemia, the precise cellular origin of IL‐6 production in CD is still debated.MethodsA series of five nodal CD of different subtypes (one UCD, two idiopathic MCDs [iMCDs], one HIV‐negative human herpesvirus 8 (HHV8)‐associated MCD, and one HIV‐positive HHV8‐associated MCD) and a non‐CD reactive control were tested using RNAscope analysis and a dual in situ hybridization (ISH)/immunohistochemistry technique, in order to quantify IL‐6 expression and its spatial distribution. Quantitative analyses of in situ mRNA were performed on digitalized slides using the HISTOQUANT software (3DHISTECH) and differences between cases were evaluated by the Kruskal‐Wallis test.ResultsRNA‐ISH documented increased IL‐6 expression in all CD lymph nodes, independently from clinical and pathological subtypes, however, the highest levels were found in HHV8+ cases and statistically significant differences in IL‐6 expression were found only between HHV8+ MCD and control case. Dual RNA‐ISH for IL6 coupled with immunohistochemistry analysis showed that IL‐6 was overexpressed in CD31‐positive endothelial cells in 5/5 CD tested cases but not in the control case.ConclusionOur findings suggest that nodal IL‐6 expression seems to be significantly upregulated in HHV8+ MCD, but a trend toward increased nodal IL‐6 expression was noticed also in UCD and iMCD‐not otherwise specified. CD31+ endothelial cells probably represent one of the major sources of IL‐6 production in the nodal microenvironment.

Efficacy and safety of orelabrutinib in relapsed/refractory idiopathic multicentric Castleman disease: A single-centre, retrospective study.

Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous lymphoproliferative disorder that lacks standardised treatment options for patients with refractory or relapsed (r/r) disease. Blocking Bruton's tyrosine kinase (BTK) has emerged as a promising therapeutic approach for iMCD without depleting B cells. This single-centre, retrospective study enrolled 10 patients with r/r iMCD who were treated with orelabrutinib, a novel, next-generation BTK inhibitor. The median age at orelabrutinib initiation was 48 (range: 31-58) years. The overall response rate was 70% (7/10 patients, 95% CI: 34.8-93.3), with 20% (n = 2) achieving complete response and 50% (n = 5) achieving partial response. The median time to response was 9.8 (range: 5.9-20.5) months. Patients in the non-responder group also demonstrated a continuous improvement in haemoglobin (91-105 g/L) and albumin (32-38 g/L) levels at month 12 of treatment despite not fulfilling response criteria. No grade 3 or higher adverse events occurred during the median time to the next treatment of 29.0 (range: 15.0-36.2) months. No patient mortality was recorded during the median follow-up duration of 32.8 (range: 15.0-36.9) months. In conclusion, orelabrutinib is a safe and effective regimen for r/r iMCD.

A Case of Idiopathic Multicentric Castleman Disease Developing in a Patient with a History of Biopsy Proven Membranous Nephropathy

Abstract Introduction/Objective Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder involving two or more lymph node sites. It is usually associated with systemic inflammatory symptoms and organ dysfunction related to hypercytokinemia. Renal involvement in iMCD has only been described in a limited number of studies and case reports. Of note, only one previous case report has described results from renal biopsies taken prior to the development of iMCD. Methods/Case Report Our patient is a 43 year old female who was first diagnosed with membranous nephropathy in early 2020. She had PLA2 R negative and Exostosin-2 positive disease. Age appropriate screening for malignancy was unremarkable. She had positive ANA titres and normal complement levels but did not meet criteria for SLE per rheumatology. Her proteinuria was improved and maintained on Lisinopril for 3 years. In October 2023, her proteinuria suddenly increased. Repeat renal biopsy was unchanged from the initial biopsy. This time, she also noticed acute swelling over her subpectoral region. PET-CT scan revealed multiple areas of avid lymphadenopathy on either sides of the diaphragm but the highest yield PET- avidity was in the subpectoral region. Biopsy of the right subpectoral lymph node was performed. According to the WHO Classification, 5th edition, diagnostic criteria for iMCD-NOS was met with the histological features displaying grade 3 plasmacytosis, grade 2 regressed germinal centers, follicular dendritic cell prominence, increased hyperplastic follicles and increased vascularity. Immunohistochemical staining for CD138 highlighted abundant plasma cells, CD21 highlighted follicular dendritic cell prominence. Vascular proliferation was seen by CD34 staining. Kappa and Lambda- ISH demonstrated polytypic staining pattern and HHV-8 was negative. Results (if a Case Study enter NA) NA Conclusion There is a significant clinical, histologic and immunologic overlap between iMCD, autoimmune or infectious disorders and malignancy. HHV-8 negative/iMCD is less well understood and has no specific biomarkers. It is important to follow the available clinicopathologic diagnostic criteria for early diagnosis, follow up and treatment. Timely recognition can help prevent multiple organ system dysfunction, systemic inflammatory symptoms, cytopenias and polyclonal lymphoproliferation. Although the pathophysiology maybe unclear, this case may also suggest that in patients with a previously diagnosed membranous nephropathy, iMCD may play a role in recurrence and worsening of the disease.

Peculiar hyper vascular manifestations in idiopathic multicentric castleman disease without tafro syndrome: a case report.

Castleman disease affects lymph nodes with abnormal cell growth. It has unicentric (single node) Castleman disease (UCD) and multicentric (multiple nodes) Castleman disease (MCD) forms. MCD is systemic, with diverse symptoms, necessitating systemic treatment. Idiopathic MCD (iMCD) clinical subtypes are divided into iMCD- not otherwise specified (NOS) and iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticular fibrosis, organomegaly). UCD, iMCD-NOS, and iMCD-TAFRO mainly exhibit histopathology of hyaline vascular type, plasma cell type, and hyper vascular type, respectively. A 21-year-old female with no comorbidities presented to the outpatient department (OPD) with left inguinal swelling, gradually growing over four years, accompanied by fever and weight loss. Her past medical history included pulmonary TB 5 years prior and miscarriages. Vitals are within normal limits. Examination revealed a tender, nonreducible inguinal lump and a smaller neck swelling. Serological tests for infections were negative. Imaging revealed enlarged lymph nodes. Biopsy confirmed Castleman disease of the hyper vascular type. We performed surgical removal of the enlarged lymph nodes followed by close regular follow-up along with potential chemotherapy for relapse. Hyper vascular type of the lymph node histology in Idiopathic multicentric Castleman disease without TAFRO syndrome must be considered a differential diagnosis in lymphoproliferative disease.

Pathophysiology, Treatment, and Prognosis of Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome: A Review.

TAFRO syndrome, first reported in 2010, is a systemic inflammatory disease with a rapid onset and potentially fatal course if not treated promptly and appropriately. The name is derived from the initial letters describing the characteristic symptoms of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly. It is sometimes considered a special subtype of idiopathic multicentric Castleman disease (iMCD) because lymph node biopsies often reveal the pathology findings seen in iMCD. However, its clinical manifestations and prognoses are not well documented. Since the clinical manifestations and prognoses of TAFRO syndrome differ significantly from those of iMCD, it is recognized as an independent disease concept and considered to partially overlap with the pathology of MCD. The pathogenesis of TAFRO syndrome remains largely unknown. Due to the lack of appropriate treatment, it often presents with multiple organ dysfunction and fatality. In this review, we summarized new findings on the pathogenesis of TAFRO syndrome and discussed current effective therapies and future treatment strategies.

Multicentric Castleman Disease: A Case Report of an Arab Female

Multicentric Castleman Disease: A Case Report of an Arab Female

An Unsuspected Case of Idiopathic Multicentric Castleman Disease (iMCD) Presenting with Renal Microangiopathy

An Unsuspected Case of Idiopathic Multicentric Castleman Disease (iMCD) Presenting with Renal Microangiopathy

HIV‐negative HHV8‐positive multicentric Castleman's disease coexistent with atypical Kaposi's sarcoma

HIV‐negative HHV8‐positive multicentric Castleman's disease coexistent with atypical Kaposi's sarcoma

Coexistence of HHV-8-Associated Plasmacytic Multicentric Castleman Disease, Kaposi's Sarcoma, and Multiple Myeloma in a HIV-Negative Patient.

Multicentric Castleman disease (MCD) is a rare, aggressive lymphoproliferative disorder. Human herpesvirus-8 (HHV-8) has an important role in the pathogenesis of the disease and its association with Kaposi's sarcoma has been reported, especially in people living with human immunodeficiency virus (HIV). In this report, we present the case of HHV-8 positive MCD accompanied by Kaposi's sarcoma and multiple myeloma in an HIV-negative patient. A 78-year-old man with Kaposi's sarcoma presented with B symptoms, pancytopenia, lymphadenopathy, and splenomegaly. The bone marrow biopsy demonstrated 70% lambda-restricted monotypic plasma cell infiltration consistent with plasma dyscrasia. Also, the patient was diagnosed with HHV-8 positive MCD as a result of inguinal lymph node excisional biopsy. Treatment was initiated including ganciclovir and methylprednisolone and followed by rituximab. The patient passed away at the 24th hour of rituximab infusion due to shock. MCD and associated malignancies are difficult to treat and have a poor prognosis. More studies and data are needed to manage these patients. Multicentric Castleman disease (MCD), often linked with human herpesvirus-8 (HHV-8) and Kaposi's sarcoma, is rare and aggressive condition, particularly in human immunodeficiency virus (HIV)-positive patients.The coexistence of MCD, Kaposi's sarcoma, and multiple myeloma is exceptionally rare in HIV-negative, immunocompetent patient.This case highlights the challenges in diagnosing and managing complex presentations of MCD and related malignancies, with poor outcomes despite treatment.

Asymptomatic multicentric Castleman disease: a potential early stage of idiopathic MCD

AbstractAccording to the diagnostic criteria for human herpesvirus 8 (HHV-8)–negative/idiopathic multicentric Castleman disease (iMCD) proposed by Castleman Disease Collaborative Network in 2017, there is a group of HHV-8–negative patients with multicentric Castleman disease (MCD) who do not have symptoms and hyperinflammatory state and do not meet the iMCD criteria. This retrospective study enrolled 114 such patients, described as asymptomatic MCD (aMCD), from 26 Chinese centers from 2000 to 2021. With a median follow-up time of 46.5 months (range, 4-279 months), 6 patients (5.3%) transformed to iMCD. The median time between a diagnosis of aMCD and iMCD in these 6 patients was 28.5 months (range, 3-60). During follow-up, 7 patients died; 3 of them died from progression of MCD. Despite that, 37.7% of patients received systemic treatment targeting MCD; this strategy was neither associated with a lower probability of iMCD transformation nor a lower death rate. The 5-year estimated survival of all patients with aMCD was 94.1% (95% confidence interval, 88.8-99.6). Transformation to iMCD was an important predictor of death (log-rank P = .01; 5-year estimated survival, 83.3%). This study suggests that patients with aMCD may represent a potential early stage of iMCD, who may not require immediate treatment but should be closely monitored.

A hypothesis on treatment strategy of severe multicentric Castleman disease with continuous renal replacement therapy.

Castleman disease (CD) is a rare lymphoproliferative disorder, with non-specific clinical manifestations, often delayed diagnosis and treatment, which pose a significant challenge in the present times. Patients diagnosed with this disease have poor prognosis due to the limited treatment options. Multicentric CD occurs at multiple lymph node stations and is associated with a proinflammatory response that leads to the development of the so-called 'B symptoms'. IL-6 seems to be a key cytokine involved in various manifestations such as lymphadenopathies, hepatosplenomegaly, and polyclonal hypergammaglobulinemia. Its levels correlate with the activity of the disease. Other consequences of MCD include increased fibrinogen levels leading to deep vein thrombosis and thromboembolic disorders, high hepcidin levels causing anaemia, elevated VEGF levels promoting angiogenesis and vascular permeability, which, along with hypoalbuminemia, induce oedema, ascites, pleural and pericardial effusions, and in severe cases, generalized anasarca. In extreme cases multiple organ failure can occur, often resulting in death. We propose the use of continuous renal replacement therapy (CRRT) in managing severe multicentric CD. Our arguments are based on the principles that CRRT is able to remove IL-6 from circulation thus attenuating the cytokine storm, can influence hepcidin levels, and reduction in oedema, and is often used in multiple organ failure to regain homeostasis control. Therefore, it could be used as a therapy or bridge therapy in severe cases. To sustain our hypothesis with evidence, we have gathered several studies from the literature confirming the successful removal of cytokines, especially IL-6 from circulation, which can be used as a starting point.

ScRNA-seq reveals the landscape of immune repertoire of PBMNCs in iMCD.

The etiology of idiopathic multicentric Castleman disease (iMCD) is poorly understood, and the identification of targetable disease mediators remains an unmet clinical need. Thus, we firstly employed single-cell RNA sequencing (scRNA-seq) to elucidate the landscape of the immune repertoire of peripheral blood mononuclear cells (PBMNCs) in iMCD and to identify additional driver cytokines/cells/pathways to address IL-6 blockade-refractory cases. We revealed that the inflammatory cytokine storm observed in iMCD was a significant phenomenon pervasive across all immune cells. B-plasma cell subsets was the main source of IL-6. The IL-6 signaling pathway was significantly activated across a spectrum of immune cells. Systemic upregulation of CXCL13 is mainly driven by peripheral helper T (Tph) and regulatory T (Treg) cells. Notably, a significant positive interaction was observed between CXCL13-expressing T cells and IL-6 signaling-activated B cells. This study provides an immune perspective on PBMNCs in iMCD at the single-cell level, unveiling pathways or targets characterized by atypical inflammatory expression that could potentially serve as promising candidates for therapeutic intervention in iMCD.

Idiopathic multicentric Castleman disease with marrow fibrosis and extramedullary hematopoiesis.

Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans. The index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation. All four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis. This case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon.