Idiopathic multicentric Castleman disease (TAFRO subtype) can mimic common differentials. High suspicion is required for chronic systemic symptoms and generalized lymphadenopathy. As fine-needle aspiration is often non-diagnostic, early excisional biopsy is important. Rituximab-based therapy represents a guideline-supported alternative when anti-IL-6 treatment is unavailable or not feasible.

Idiopathic multicentric Castleman disease (iMCD) is a heterogeneous cytokine storm disorder involving systemic inflammation, multicentric lymphadenopathy with characteristic histopathology, and life-threatening multiple organ dysfunction. Patients can present with symptoms ranging from thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), reticulin myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO) to thrombocytosis, hypergammaglobulinemia, and plasmacytosis (iMCD-IPL), with patients not falling into either group (iMCD-NOS). The molecular mechanisms across the clinical subtypes have not been elucidated and new effective treatments are needed. Here, we performed bulk RNA sequencing and targeted gene expression quantification in lymph node tissue from multiple iMCD clinical subtypes, pathologically related disorders, and controls. We identified 249 upregulated and 42 downregulated genes in iMCD-TAFRO lymph node tissue, which were enriched in the following pathways: angiogenesis, cell proliferation, and various aspects of the humoral and innate immune response. The targeted gene expression analysis revealed shared differentially expressed genes (DEGs) across all three iMCD clinical subtypes, including SPP1, XBP1, PRDM1, and CLU. We identified unique DEGs in each iMCD clinical subtype, including PLA2G2A, MSR1, IL8 (iMCD-TAFRO), IL9, KIR3DL1, IL18RAP (iMCD-IPL), and IL7, TLR8, and CX3CR1 (iMCD-NOS). Since Clusterin (CLU) was significantly upregulated in iMCD but not in related conditions, we performed immunohistochemistry and observed that Clusterin is elevated in the germinal center and mantle zone regions of iMCD patient lymph nodes. A composite model incorporating CLU expression in these lymph node compartments with germinal center features demonstrated strong performance in differentiating iMCD from selected lymphadenopathies. Together, this work identified pathways dysregulated in iMCD lymph nodes and suggests that Clusterin, particularly when integrated with germinal center features, could be a novel biomarker.

TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, renal dysfunction, and myelofibrosis, and its follows a rapidly fatal clinical course. A few cases of TAFRO syndrome complicated by adrenal hemorrhage were recently reported; however, its pathogenetic significance remains largely unclear.The present case was a 59-year-old man presenting with left lower back pain. Imaging studies revealed left adrenal hemorrhage. Although an elevated C-reactive protein level was observed in the initial visit, there were no obvious abnormalities in the platelet count, renal function, or coagulation profile. Subsequently, fluid retention and renal dysfunction progressed rapidly, and thrombocytopenia emerged, leading to a diagnosis of TAFRO syndrome. Treatment including glucocorticoid therapy was initiated, but was ineffective; the disease progressed rapidly, and the patient succumbed to multiple organ failure. Autopsy revealed findings consistent with TAFRO syndrome in small lymph nodes and those suggestive of thrombotic microangiopathy in renal glomeruli.Based on these findings, adrenal hemorrhage may occur as an initial presentation prior to the manifestation of the full systemic picture of TAFRO syndrome. Furthermore, the disease progressed rapidly to a severe state in a short period without initial thrombocytopenia-which complicated the diagnosis-and demonstrated resistance to conventional treatments including glucocorticoids, which underscores the importance of early recognition and therapeutic intervention.

A woman in her 40s of South Asian ethnic origin presented with progressive multisystem disease including chronic distal neuropathy, constitutional decline, lymphadenopathy and serosal effusions. Initial evaluation suggested infection, particularly tuberculosis, causing diagnostic uncertainty. Investigations identified biclonal lambda-restricted paraproteinaemia, generalised lymphadenopathy and mixed axonal demyelinating polyneuropathy. Early lymph node biopsies were inconclusive, but an excision biopsy later confirmed Castleman disease. Bone marrow examination demonstrated a lambda-restricted clonal plasma cell disorder. With neuropathy, monoclonal gammopathy, organomegaly, endocrinopathy, Castleman disease, extravascular volume overload and elevated vascular endothelial growth factor (VEGF), polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes (POEMS) syndrome was diagnosed.The patient received daratumumab, bortezomib and dexamethasone, followed by autologous stem cell transplantation, achieving biochemical remission with normalised VEGF, though neuropathy persisted.This case highlights the diagnostic and treatment challenges when associated with Castleman disease and latent tuberculosis. Earlier diagnosis can prevent further neurological damage in POEMS.

Peripancreatic unicentric Castleman disease is rare and may mimic a primary pancreatic neoplasm because it often presents as a well-circumscribed hypervascular mass. We report a 26-year-old woman with type 2 diabetes mellitus in whom an incidentally detected upper abdominal mass was initially considered to arise from the pancreatic body. Computed tomography and magnetic resonance imaging showed a sharply marginated hypervascular lesion with diffusion restriction at the superior border of the pancreatic body, leading to a preoperative suspicion of pancreatic neuroendocrine tumor. Laparoscopic exploration revealed a well-encapsulated mass in the lesser sac closely abutting the superior surface of the pancreas. A clear dissection plane between the lesion and the pancreatic parenchyma allowed complete excision without pancreatic resection or splenectomy. Histopathological examination confirmed hyaline vascular-type unicentric Castleman disease. The postoperative course was uneventful, and no residual or recurrent lesion was detected during 1 year of follow-up; glycemic status also remained stable. This case highlights that close proximity of a hypervascular mass to the pancreas does not necessarily indicate pancreatic origin. Careful multiplanar imaging and direct intraoperative assessment of the lesion-pancreas interface may help determine the appropriate surgical extent and avoid unnecessary pancreatic resection when complete excision is technically feasible.

Kimura disease (KD) is a rare chronic inflammatory proliferative disorder. Inguinal involvement is particularly uncommon, and its clinical and imaging appearances may mimic lymphoproliferative disease. We report a 38-year-old man (body mass index, 29.4 kg/m[2]) with a pruritic right inguinal mass present for more than 5 years. A previous diagnosis of Castleman disease (CD) had led to chemotherapy and surgery without satisfactory control. Ultrasonography showed a 70 × 32 × 46 mm heterogeneous hypoechoic subcutaneous mass containing scattered internal cord-like hyperechoic bands. Color Doppler imaging demonstrated abundant central arborizing intralesional vascularity. The absolute peripheral blood eosinophil count was 3.77 × 10[9]/L (32.6%). Noncontrast computed tomography demonstrated the dominant right inguinal mass and additional nodal lesions. Histopathologic examination after complete excision showed lymphoid follicular hyperplasia, extensive interfollicular eosinophilic infiltration, and eosinophilic microabscesses, confirming KD. This case expands the sonographic spectrum of inguinal KD and suggests that the combination of marked eosinophilia, internal cord-like hyperechoic bands, and central arborizing vascularity may help distinguish KD from CD before surgery.

Castleman disease (CD) comprises a heterogenous group of rare nonmalignant lymphoproliferative disorders. CD is classified as unicentric (UCD) and multicentric CD (MCD) depending on the number of lymph node region involvement. Oligocentric CD (OligoCD) is a recently validated provisional subtype with intermediate clinical features and outcomes. MCD is further subcategorized by etiology into three distinct entities: (1) human herpesvirus 8 (HHV-8) associated (HHV-8+) MCD, (2) idiopathic MCD (iMCD), (3) polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes (POEMS)-associated MCD. Idiopathic MCD itself encompasses three clinical subtypes: iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly), idiopathic plasmacytic lymphadenopathy (iMCD-IPL), and iMCD-NOS (not otherwise specified). Recent advances suggest that CD comprises biologically distinct entities with unique genetic landscapes, cellular origins, and mechanisms underlying interleukin-6 production. MCD is thought to arise from multifactorial mechanisms, including autoimmune dysregulation, chronic inflammatory processes, and paraneoplastic phenomena. The diagnosis of CD remains challenging due to its overlapping features with a broad range of reactive and malignant disorders, as well as its potential coexistence with other underlying conditions. This review focuses on the cell origins and biological mechanisms underlying CD, with particular emphasis on distinguishing CD from conditions with overlapping features, thereby enhancing our understanding of its pathogenesis and disease biology.

A man in his early 60s presented initially with abdominal symptoms, nutritional deficiencies, severe hypoalbuminaemia, thrombocytopenia and marked inflammation, without clinically apparent lymphadenopathy. Over subsequent hospitalisations, he developed progressive anasarca, pleural and peritoneal serositis, bicytopenia and renal dysfunction. Cardiac, renal, gastrointestinal, infectious, neoplastic and autoimmune explanations were investigated but did not account for the evolving multisystem picture. Lymphadenopathy became evident only later on positron emission tomography-CT, providing the diagnostic pivot. Lymph node assessment, persistent hyperinflammation and the evolving clinical pattern supported idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever/hyperinflammation, renal dysfunction and organomegaly features (iMCD-TAFRO). Treatment with corticosteroids and siltuximab was followed by clinical and biochemical improvement. This case illustrates how TAFRO syndrome may become recognisable before lymphadenopathy makes Castleman disease an obvious consideration.

Kaposi sarcoma (KS) is an angioproliferative neoplasm driven by human herpesvirus 8 (HHV-8), most commonly occurring in immunocompromised individuals, particularly in association with HIV infection. Although it classically presents with characteristic cutaneous or mucocutaneous lesions, nodal-predominant disease without skin involvement is uncommon and may pose a significant diagnostic challenge. We report the case of a 26-year-old man with recently diagnosed HIV infection and no prior antiretroviral therapy (ART) who presented with a two-week history of persistent fever, constitutional symptoms, abdominal pain, and progressive intolerance to oral intake. Initial evaluation revealed hemodynamic instability, severe microcytic anemia, marked thrombocytopenia, and progressive renal dysfunction. Imaging demonstrated generalized lymphadenopathy involving multiple nodal chains, bilateral pleural effusions, hepatosplenomegaly, and free intra-abdominal fluid, raising concern for a disseminated infectious, lymphoproliferative, or neoplastic process. CD4+ T-cell count and HIV viral load were not available in the clinical records reviewed; therefore, the degree of HIV-associated immunosuppression could not be quantitatively established. Given the persistence and progression of systemic manifestations, an excisional inguinal lymph node biopsy was performed. Histopathological examination demonstrated spindle-cell proliferation with irregular slit-like vascular spaces and erythrocyte extravasation. Immunohistochemical analysis showed nuclear positivity for HHV-8 latent nuclear antigen-1 (LNA-1), together with positivity for endothelial markers, confirming KS. No cutaneous or mucosal lesions suggestive of KS were identified during the clinical course, supporting an atypical presentation with predominant nodal involvement. The patient received supportive inpatient management, including hemodynamic stabilization and transfusional support. Despite an initial period of partial clinical stabilization, he subsequently developed acute respiratory failure with progressive clinical deterioration and died during the index hospitalization before the planned HIV- and KS-directed therapeutic strategy could be completed. Nodal KS without cutaneous involvement is an uncommon and potentially underrecognized presentation that may mimic HIV-associated lymphoma, disseminated opportunistic infections, and HHV-8-associated multicentric Castleman disease. This case emphasizes that KS should remain in the differential diagnosis of persistent lymphadenopathy and systemic manifestations in patients with HIV even when characteristic skin lesions are absent. Because imaging findings are nonspecific, early tissue biopsy with histopathological examination and HHV-8 immunohistochemistry is essential for definitive diagnosis. This paper was published earlier on the Research Square preprint server on April 14, 2026 (DOI: 10.21203/rs.3.rs-9363985/v1).

Idiopathic multicentric Castleman disease can rarely present with systemic inflammation and erosive seronegative polyarthritis. Awareness of this association helps prevent misdiagnosis and ensures appropriate immunosuppressive management based on clinicopathological and immunohistochemical correlation. Careful multidisciplinary evaluation is essential to distinguish this uncommon presentation from autoimmune and lymphoproliferative disorders in clinical practice.

HHV8-positive diffuse large B-cell lymphoma (HHV8+ DLBCL) is a rare and aggressive lymphoma frequently associated with multicentric Castleman disease. Population-based data remain limited. Using the National Cancer Database (2004-2023), we analyzed 262 patients with histologically confirmed HHV8+ DLBCL (ICD-O-3 9738/3), representing the largest cohort to date. The cohort was predominantly male (76.7%), White (66.0%), with a mean age of 52.6 years. The primary site was nodal in 78.6%. Systemic therapy was administered in 72.9% of patients. Median overall survival was 133 months, with 1-, 3-, and 5-year survival rates of 68.2%, 63.1%, and 59.9%, respectively. On multivariable Cox regression, age ≥60 years, Charlson-Deyo score ≥1, HIV-positive status, and lack of systemic therapy and surgery to the primary site were independently associated with worse overall survival. In a subgroup analysis restricted to patients with known HIV status (n = 113), HIV-positive status was the only variable significantly associated with worse overall survival on univariable analysis.