Idiopathic Multicentric Castleman 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.

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.

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.

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

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.

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.

MPN-307 Systemic AA Amyloidosis as a Complication of Idiopathic Multicentric Castleman's Disease

MPN-307 Systemic AA Amyloidosis as a Complication of Idiopathic Multicentric Castleman's Disease

Diagnostic challenges in patients with Castleman disease, a single center experience from Hungary.

Castleman disease is a rare and atypical lymphoproliferative disorder characterized by diverse clinical manifestations. It has both unicentric and multicentric forms, the latter with further subdivisions, i.e., human herpesvirus 8-associated and idiopathic forms. The diagnosis of Castleman disease is often delayed, as it is rare, and because it shares clinical features with different autoimmune, inflammatory, and malignant lymphoproliferative disorders. The first-line treatment in unicentric form is mainly surgical, while in idiopathic Castleman disease, anti-interleukin-6 treatment is the therapy of choice. In virus-associated diseases, antiretroviral therapy and rituximab are recommended. In Hungary, only a few cases of Castleman disease have been published. This report presents our twodecades of experience in the challenging diagnosis and management of this rare disorder, most properly underdiagnosed in Hungary. We provide insights into seven unicentric and five idiopathic multicentric Castleman disease cases, the latter ones especially highlighting the diagnostic and therapeutic challenges due to the variable and unique clinical features both of patients and diseases, e.g., bronchiolitis obliterans, stage IV diabetic renal failure, anti-HBc positivity, siltuximab treatment period, respectively.

Epstein-Barr Virus-Encoded RNA-Positive Lymphocytes in Bone Marrow and Lymph Nodes in an Autopsy Case of TAFRO Syndrome.

A 55-year-old man was admitted to the hospital with vomiting, diarrhoea, and chest pain. Upon examination, he exhibited signs of increased inflammatory response, acute kidney injury, and thrombocytopenia, leading to a diagnosis of TAFRO syndrome, which was supported by the clinical evidence of generalized lymphadenopathy, pleural effusion, and hepatosplenomegaly. Despite receiving intensive multimodal immunosuppressive therapy, including glucocorticoid pulse therapy (methylprednisolone 1,000 mg/day), tocilizumab, and cyclosporine in the intensive care unit, the patient showed minimal response and succumbed to the disease on the seventh day of hospitalization. Histopathological analysis of the lymph nodes revealed idiopathic multicentric Castleman disease (iMCD)-like features, and Epstein-Barr virus-encoded RNA (EBER) in situ hybridization identified multiple EBER-positive cells. These findings highlight the elusive pathogenic mechanism of TAFRO syndrome and the potential resistance of some patients to standard treatments such as tocilizumab. The presence of EBER-positive cells in lymph nodes or bone marrow may serve as an indicator of disease severity and treatment resistance. Therefore, histopathological detection of EBER-positive cells may help predict responsiveness to conventional treatments, disease severity, and prognosis in patients with TAFRO syndrome.

Idiopathic multicentric Castleman disease-TAFRO after COVID-19: A case report.

TAFRO syndrome, a rare disease characterised by thrombocytopaenia, anasarca, fever, reticulin fibrosis, and organomegaly, is thought to be caused by hypercytokinaemia. It is a heterogeneous clinical entity, and a recent comprehensive international definition defined TAFRO syndrome with lymph node histopathology consistent with idiopathic multicentric Castleman disease (iMCD) as iMCD-TAFRO. Herein, we present a rare case of iMCD-TAFRO following coronavirus disease 2019 (COVID-19) infection. A 62-year-old Japanese woman, initially diagnosed with COVID-19, developed a persistent fever and fluid retention, prompting the diagnosis of iMCD-TAFRO. Following the initiation of prednisolone and cyclosporine, her symptoms gradually resolved. Therefore, we discuss the potential pathophysiological link between COVID-19 and iMCD-TAFRO, emphasising the role of cytokine storms. This case report highlights the importance of recognising the spectrum of inflammatory states after COVID-19 and differentiating iMCD-TAFRO after COVID-19 from the COVID-19 cytokine storm syndrome.

An unusual case of HHV-8 negative, idiopathic, multicentric Castleman disease following chronic lymphocytic leukaemia

Background: Castleman disease is a rare condition characterised by polytypic lymphocytes proliferation and lymphadenopathy generally with a benign course. Whereas high grade lymphoma (Richter syndrome) is a classical complication seen in chronic lymphocytic leukaemia with a poor outcome, benign conditions mimicking this entity are infrequent. Case description: We describe the case of an 81-year-old Caucasian male who developed a human herpesvirus-8 (HHV-8)–negative, idiopathic multicentric Castleman disease (iMCD) following a treated Binet C chronic lymphocytic leukaemia (CLL). The clinical and radiological pattern raised initially the suspicion of a classical Richter transformation. Blood analysis showed auto-immune haemolytic anaemia and thrombocytopenia. He had normal immunoglobulin levels. The anatomopathological analysis of a cervical adenomegaly showed hypervascularisation and a polytypic plasmocytic proliferation compatible with a plasmocytic iMCD type. Interestingly, bone marrow examination showed reticuline fibrosis but, in the absence of anasarca or generalised oedema, we were not allowed to conclude to the diagnosis of a TAFRO syndrome. We exclude all other mimicking conditions, comprising haematological malignancies, infections, and auto-immune diseases He was first treated with corticosteroids with poor results but dramatically responded to tocilizumab (anti-Il6). Conclusion: To our knowledge, this the first case described of a Castleman disease following CLL and surprisingly mimicking Richter syndrome. Clinicians should be aware of this rare misleading condition.

Delayed diagnosis of TAFRO syndrome: A case report.

TAFRO syndrome is a systemic inflammatory disorder, manifesting as thrombocytopenia (t), anasarca (a), fever (f), reticulin myelofibrosis/renal insufficiency (r), and organomegaly (o), and considered as a unique clinical subtype of idiopathic multicentric Castleman disease (iMCD). Such syndrome gave rise to a clinical picture similar to that of either a connective tissue disease or an autoimmune disease. A Chinese young female initially presenting with arthralgia, Raynaud phenomenon, generalized edema, and a positive anti-small nuclear ribonucleoprotein particle antibody was diagnosed as mixed connective tissue disease. The kidney biopsy showed thrombotic microangiopathy. Bone marrow smear showed bone marrow hyperplasia and biopsy revealed suspected light chain restricted expression, megakaryocyte proliferation, and moderate to severe bone marrow fibrosis. A lymph node biopsy was conducted and the histopathological findings were consistent with the subtype of mixed Castleman disease. The clinical symptoms were relieved after regular chemotherapy. After above examination results and clinical manifestations, the final diagnoses was TAFRO syndrome. The she was started on chemotherapy with bortezomib, cyclophosphamide, and dexamethasone. After chemotherapy, symptoms such as thrombocytopenia, hematuria and proteinuria disappeared, lymphadenopathy and VEGF level decreased, and bone marrow fibrosis relieved. Our case illustrated the first cases of shared characteristics of mixed connective tissue disease and iMCD-TAFRO syndrome. Cytokines may play a role in the shared pathogenicity of the iMCD-TAFRO syndrome and systemic autoimmune diseases. Therapy directly against inflammatory factors such as corticosteroids or chemotherapy have an important therapeutic implication.

Internal Psychometric Validation of an International Burden of Illness Survey for Idiopathic Multicentric Castleman Disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare, chronic, debilitating lymphoproliferative disorder where the mainstay of treatment is symptom management. Our recent international patient survey showed that patients with iMCD have a high symptom burden that has a significant negative patient-reported impact on several aspects of daily life. As part of our ongoing work towards the development of an iMCD symptom burden scale, assessing the survey's psychometric properties is a critical step in understanding its adequacy, relevance, and usefulness. As iMCD is a rare disease, there are challenges to conducting such psychometric analyses which we describe. As part of the exploratory psychometric analysis, three a priori hypothesis sets (HS) were generated by interviewing an iMCD-experienced clinician, a patient, and a caregiver to explore the iMCD patient survey's internal construct validity, given no gold standard iMCD measure exists for external construct validation. HS-1hypothesized that a convergent or discriminant relationship exists with the patients' self-assessment of symptom effect on daily life between two potentially related or unrelated symptoms, respectively. HS-2hypothesized that having a greater number of symptoms has a positive convergent relationship with the patients' assessment of symptoms' effect on daily life. Finally, HS-3hypothesized that patients receiving treatment versus no treatment was associated with patients reporting less effect of symptom burden on their daily life. Spearman's rank absolute correlation strength (ACS) was used for HS-1 and HS-2 (convergent relationship, ACS ≥ 0.3 and pvalue < 0.05; divergent relationship, ACS < 0.3), and Cohen's d to quantify standardized absolute effect sizes (AES) for HS-3 (AES ≥ 0.5 and pvalue < 0.05). Our analyses partially supported HS-1. None of the three positive convergent relationships were supported. Of the six discriminant relationships, only dizziness with impaired cognitive function and tiredness with dizziness were supported. HS-2 analyses showed there was convergent validity between the number of symptoms and their effect on aspects of daily life. HS-3 analyses did not provide evidence to support the hypothesis. These internal psychometric construct analyses provide initial support for the bespoke iMCD patient survey and will guide additional work towards the development of the first iMCD-specific symptom burden scale.

Idiopathic multicentric Castleman's disease. Features of radiological imaging with postprocessing. Presentation of own observation

Idiopathic multicentric Castleman's disease. Features of radiological imaging with postprocessing. Presentation of own observation