Castleman's Disease Research Articles

Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives.

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman's disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman's disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Myasthenia gravis with Castleman disease: A case report with review of literature.

Myasthenia gravis is an autoimmune disorder caused by the formation of autoantibodies directed against the synapses of neuromuscular junction. It is most commonly associated with other non-thymomatous lesions. Castleman disease is one of them, which is a benign lymphoproliferative disorder of uncertain origin. Only eight cases of myasthenia gravis associated with Castleman disease have been described so far. Here, we take the opportunity to describe a case of myasthenia gravis with Castleman disease simulating thymoma clinically and radiologically along with review of literature of this rare association. Patient developed myasthenic crisis in the immediate post-operative period which is more common in myasthenia gravis with Castleman disease rather than myasthenia gravis with thymoma.

Castleman disease with modest T-lymphoblastic proliferation

Castleman disease with modest T-lymphoblastic proliferation

The Interplay between KSHV Infection and DNA-Sensing Pathways

During viral infection, the innate immune system utilizes a variety of specific intracellular sensors to detect virus-derived nucleic acids and activate a series of cellular signaling cascades that produce type Ⅰ IFNs and proinflammatory cytokines and chemokines. Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus that has been associated with a variety of human malignancies, including Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Infection with KSHV activates various DNA sensors, including cGAS, STING, IFI16, and DExD/H-box helicases. Activation of these DNA sensors induces the innate immune response to antagonize the virus. To counteract this, KSHV has developed countless strategies to evade or inhibit DNA sensing and facilitate its own infection. This review summarizes the major DNA-triggered sensing signaling pathways and details the current knowledge of DNA-sensing mechanisms involved in KSHV infection, as well as how KSHV evades antiviral signaling pathways to successfully establish latent infection and undergo lytic reactivation.

Evaluation of two commercial diagnostic methods for HHV-8 viral load assessment

ObjectivesHuman herpesvirus-8 (HHV-8) can cause Kaposi's sarcoma or B lymphoproliferative disorders such as multicentric Castleman disease. Patient follow-up is based on assessing the HHV-8 viral load, which is usually achieved using real-time polymerase chain reaction (PCR). The HHV-8 Premix r-gene kit (BioMérieux) was used by some laboratories in the past, but BioMérieux ceased the production and distribution of this kit in 2021-2022. Other kits need to be tested so that they can be used for diagnostic purposes. Here we evaluated two commercial kits: HHV8 ELITe MGB Kit (ELITech) and Quanty HHV-8 (Clonit) and compared them with the HHV-8 Premix r-gene kit. MethodsWe used whole blood samples that had previously been tested with the HHV-8 Premix r-gene kit for diagnostic purposes. Overall, 46 samples (37 HHV-8-positive and 9 HHV-8-negative) were tested with the ELITe MGB Kit and 37 (29 HHV-8-positive and 8 HHV-8-negative) with the Quanty HHV-8 kit. The different methods were compared using Bland-Altman and Passing-Bablok tests with Analyse-it software. ResultsQualitative results were concordant except for one HHV-8 low-positive sample that was found to be negative by the ELITe MGB Kit. The quantitative results were also concordant; both kits showed mean differences of 0.58 log10 copies/ml and 0.73 log10 copies/ml, respectively, compared to the Premix r-gene kit. ConclusionsBoth the methods tested produced acceptable results and could be used for diagnostic purposes. It should be remembered that there is no international standard for HHV-8 quantification and that patients should always be followed using the same method.

Transoral robotic surgery tongue base debulking in Castleman's disease.

Transoral robotic surgery tongue base debulking in Castleman's disease.

The Etiologic Landscape of Lymphoproliferation in Childhood: Proposal for a Diagnostic Approach Exploring from Infections to Inborn Errors of Immunity and Metabolic Diseases.

Lymphoproliferation is defined by lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytic organ and tissue infiltration. The most common etiologies of lymphoproliferation are represented by infectious diseases and lymphoid malignancies. However, it is increasingly recognized that lymphoproliferative features can be the presenting sign of rare conditions, including inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Among IEI, lymphoproliferation is frequently observed in autoimmune lymphoproliferative syndrome (ALPS) and related disorders, common variable immunodeficiency (CVID), activated phosphoinositide 3-kinase δ syndrome, and Epstein-Barr virus (EBV)-related disorders. Gaucher disease and Niemann-Pick disease are the most common IEMs that can present with isolated lymphoproliferative features. Notably, other rare conditions, such as sarcoidosis, Castleman disease, systemic autoimmune diseases, and autoinflammatory disorders, should be considered in the differential diagnosis of patients with persistent lymphoproliferation when infectious and malignant diseases have been reasonably ruled out. The clinical features of lymphoproliferative diseases, as well as the associated clinical findings and data deriving from imaging and first-level laboratory investigations, could significantly help in providing the correct diagnostic suspicion for the underlying etiology. This paper reviews the most relevant diseases associated with lymphoproliferation, including infectious diseases, hematological malignancies, IEI, and IEM. Moreover, some practical indications to orient the initial diagnostic process are provided, and two diagnostic algorithms are proposed for the first-level assessment and the approach to persistent lymphoproliferation, respectively.

Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study.

Refractory/relapsed idiopathic multicentric Castleman disease (R/R iMCD) has limited treatment options. With studies showing increased mTOR activation in iMCD patients, sirolimus becomes an attractive and promising therapy for R/R iMCD. Here we report the results of a retrospective study involving 26 R/R iMCD patients treated with sirolimus-containing regimen. The median age at sirolimus initiation was 40.5 years (23-60), with a median prior treatment line of 2 (1-5). 18 patients (69.2%) achieved symptomatic and biochemical response, with a median time to at least overall partial remission of 1.9 months (0.5-14.6). The median follow-up time from sirolimus initiation was 11.7 months (1.6-50.7) and the median time to next treatment (TTNT) was 46.2 months. No patients died at the end of follow-up. Most of the patients in the cohort are in ongoing responses and continue sirolimus therapy. Sirolimus is well tolerated with minor adverse effects. In conclusion, sirolimus is effective for R/R iMCD patients with good tolerance.

A large inflammatory fibroid polyp of jejunum with unusual presentation: very difficult to diagnosis in paediatric patient

Inflammatory fibroid polyps (IFP), also known as Vanek tumours, are one of the rarest groups of gastrointestinal tract polyps. They represent 0.1-3.0% of all polyps in this organ system. Most common location is the stomach, mainly the antrum (70%), ileum (19%), and colon (6%). Large polyps of the stomach can cause intermittent obstruction, described as “ball valve syndrome”. This case report, reported in SMS medical college Jaipur in one year six months old child. We report a case of a 1 year 6 months female child with complaint of abdominal lump noted since 7 days, due to this reduced oral intake. On examination single, around 5×5 cm size non-tender lump is situated in left hypogastric region. On CECT abdomen shows mesenteric origin, may be desmoid tumour, Castleman disease, mesenteric haemangioma or inflammatory myo-fibroblastic tumour. Further MRI abdomen suggestive of inflammatory myo-fibroblastic tumour or NHL. Tumour marker study shows serum ferritin and LDH level raised. On exploration revealed a single, 6×5×4 cm lobulated jejunal mass encircle the jejunum, for this resection and anastomosis done. On histopathological report, suggestive of inflammatory fibroid polyp. Patient discharged successfully on 6th pod without any complication. Exploration done and a mass, which encircle the jejunum found. Resection and anastomosis done and patient discharged on 6th pod without any complications. Such an occurrence was incidental in the reported case, which can confuse our diagnosis, so knowledge about this type of disease is very important, especially in paediatrics population.

Cardiac tamponade: A rare manifestation of Castleman disease.

Cardiac tamponade: A rare manifestation of Castleman disease.

Can We Differentiate Between Primary Sjögren Syndrome and Idiopathic Multicentric Castleman Disease Based on the Characteristics of Pulmonary Cysts?

To identify radiological characteristics that could help differentiate cystic lung diseases between primary Sjögren syndrome (pSS) and idiopathic multicentric Castleman disease (iMCD). Patients with pSS or iMCD who had cysts were enrolled. Cyst characteristics (number, size, morphology, and distribution) and other accompanying manifestations (nodules, ground-glass opacities, calcification, and thickening of the bronchovascular bundles and interlobular septa) were compared between them. Eleven patients with pSS and 25 patients with iMCD were eligible for our study. Eleven patients with pSS (100.0%) and 23 patients with iMCD (92.0%) had round or oval cysts. None of the patients with pSS had irregular cysts, but 21 (84.0%) patients with iMCD had irregular cysts ( P = 0.005). Smooth-walled cysts were present in 11 patients with pSS (100.0%) and 18 patients with iMCD (72.0%). Only 1 patient with pSS (9.1%) exhibited non-smooth-walled cysts, whereas 23 patients with iMCD (92.0%) had non-smooth-walled cysts ( P = 0.003). The presence of nodules was common in both groups ( P = 1.000). However, the nodules were more likely to be larger and more numerous in patients with iMCD ( P < 0.001). Cysts with mural nodules (52.2%) and central nodules (47.8%) were only observed in iMCD ( P = 0.007). Although regular and smooth-walled cysts were common in the 2 diseases, irregular and non-smooth-walled cysts were more often associated with iMCD than pSS. Nodules in iMCD tended to be larger and more numerous, and a close positional relationship between nodules and cysts was only observed in iMCD.

Primary Castleman's disease in the hepatic parenchyma: A case report and literature review

Primary Castleman's disease in the hepatic parenchyma: A case report and literature review

Analysis of the interaction between the ORF42 and ORF55 proteins encoded by Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. The tegument is a structure that is unique to herpesviruses that includes host and viral proteins, including the viral ORF42 and ORF55 proteins. Alphaherpesvirus tegument proteins have been well studied, but much is unknown regarding KSHV. Here, we report an interaction between the ORF42 and ORF55 proteins. ORF55 interacted with and recruited ORF42 from the nucleus to the cytoplasm. When ORF42 and ORF55 were expressed simultaneously in cultured cells, the expression level of these two viral proteins was higher than when either was expressed independently. ORF55, but not ORF42, was polyubiquitinated, suggesting that an unidentified regulatory mechanism may be present. A recombinant virus with an ectopic stop codon in ORF42 exhibited normal replication of genomic DNA, but fewer virus particles were released with the recombinant than with the wild-type virus. A unique R136Q mutation in ORF42, which is found in a KSHV strain that is prevalent on Miyako Island, Okinawa Prefecture, Japan, further increased the expression of ORF42 and ORF55 when these proteins were expressed simultaneously. However, the ORF42 R136Q mutation did not affect the localization pattern of ORF42 itself or of ORF55. In addition, experiments with a recombinant virus possessing the ORF42 R136Q mutation showed lower levels of production of the mutant virus than of the wild-type virus, despite similar levels of genome replication. We suggest that the R136Q mutation in ORF42 plays an important role in ORF55 protein expression and virus production.

A rare presentation of Castleman disease

A rare presentation of Castleman disease

Idiopathic multicentric Castleman disease and its rare association with peripheral neuropathy and stroke

Idiopathic multicentric Castleman disease and its rare association with peripheral neuropathy and stroke

Radiological Imaging Findings of Adrenal Abnormalities in TAFRO Syndrome: A Systematic Review.

This systematic review article aims to investigate the clinical and radiological imaging characteristics of adrenal abnormalities in patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome. We searched the literature in PubMed, the Cochrane Library, and the Web of Science Core Collection. Ultimately, we analyzed 11 studies with 22 patients plus our 1 patient, totaling 23 patients. The mean age was 47.0 ± 12.6 years. There were 20 male and 3 female patients, respectively. The histopathological analysis of lymph nodes was conducted in 15 patients (65.2%), and the diagnosis was consistent with TAFRO syndrome in all 15 patients. Among the 23 patients, 11 patients (18 adrenal glands) showed adrenal ischemia/infarction, 9 patients (13 adrenal glands) showed adrenal hemorrhage, and 4 patients (7 adrenal glands) showed adrenomegaly without evidence of concurrent ischemia/infarction or hemorrhage. One patient demonstrated unilateral adrenal hemorrhage and contralateral adrenomegaly. In patients with adrenal ischemia/infarction, the adrenal glands displayed poor enhancement through contrast-enhanced computed tomography (CT). In patients with adrenal hemorrhage, the adrenal glands revealed high attenuation through non-enhanced CT and hematoma through magnetic resonance imaging. Adrenomegaly, with or without adrenal ischemia/infarction or hemorrhage, was observed in all patients (23/23, 100%). The subsequent calcification of the affected adrenal glands was frequently observed (9/14, 64.3%) when a follow-up CT was performed. Abdominal pain was frequent (15/23, 65.2%), all of which occurred after the disease's onset, suggesting the importance of considering TAFRO syndrome as a cause of acute abdomen. Given the absence of evidence of adrenal abnormalities in non-TAFRO-idiopathic multicentric Castleman disease (iMCD), they may serve as diagnostic clues for differentiating TAFRO syndrome from non-TAFRO-iMCD.

VEXAS syndrome: A new mimicker of idiopathic multicentric Castleman disease

IntroductionIdiopathic Multicentric Castleman Disease (iMCD) is a complex and poorly understood pathophysiological entity, which encompasses a variety of conditions and can mimic or be associated with autoimmune/autoinflammatory diseases, making it challenging to diagnose and treat. Vacuoles, Enzyme E1, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder associated with hematological abnormalities and caused by acquired somatic mutations in the ubiquitin-like modifier activating enzyme 1 gene (UBA1) which shares several common clinical and biological signs with iMCD. In this article, we report a patient with VEXAS syndrome initially presenting as iMCD, questioning the link between these two entities. Case descriptionWe report here a patient initially presenting as iMCD, proved on lymph node histology, which turns out to have a mutation at the splice acceptor site of exon 3 of UBA1 exhibiting VEXAS syndrome with Castleman-like lymph node. ConclusionThis is only the second case of VEXAS syndrome presenting as iMCD. VEXAS syndrome should therefore be considered in the presence of iMCD suspicion, including in cases of compatible histology.

Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy

AbstractIdiopathic multicentric Castleman disease (iMCD) is an inflammatory disease associated with a cytokine storm, activation of the PI3K/AKT/mTOR pathway, coagulopathy, and increased risk of thrombosis. The mechanisms underlying these pathologic processes remain elusive. We studied novel markers of mTOR activation and thrombosis in 1 patient with typical features of iMCD with TAFRO (thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, and organomegaly) syndrome (iMCD-TAFRO). Plasma levels of SVEP1 (Sushi, von Willebrand factor type A, epidermal growth factor, and pentraxin domain–containing 1 protein), a newly identified mTOR activator associated with cardiovascular diseases and dementia, in addition to cytokines, chemokines and components of the coagulation cascade and complement system were evaluated by enzyme-linked immunosorbent assay (ELISA) and arrays. Compared with healthy controls, a 15-fold increase in SVEP1 was observed. High levels of factor VIIa/antithrombin and microparticles expressing functional tissue factor (TF) were detected. The anticoagulants thrombomodulin and soluble endothelial protein C receptor were elevated, indicating shedding from endothelial cells. Plasminogen activator inhibitor 1 was increased, consistent with hypofibrinolysis, whereas high levels of C3b and C5a are in keeping with complement activation. Furthermore, markers of endothelial cell activation (e.g. von Willebrand factor, angiopoietin-2), cell adhesion molecules, and angiogenesis mediators were upregulated. SVEP1 emerges as a potential mechanism of mTOR activation in iMCD-TAFRO, while multiple pathways influence coagulopathy. Immunothrombosis emerges as a potential therapeutic target for iMCD.

Hodgkin Lymphoma-related Inflammatory Modification-displayed Castleman Disease-like Histological Features and Positron Emission Tomography/Computed Tomography Usefulness for the Differential Diagnosis.

Hodgkin lymphoma (HL) and idiopathic multicentric Castleman disease (iMCD) are markedly different conditions. However, in some cases, histological similarities caused by elevated cytokines, including interleukin-6, can lead to a misdiagnosis of HL as Castleman disease (CD). We herein report a patient with HL who had been diagnosed with CD by an expert panel and for whom an additional biopsy was useful for determining the correct diagnosis. Furthermore, we analyzed the positron emission tomography/computed tomography findings at the diagnosis and found that the maximum standardized uptake value was useful for distinguishing HL from iMCD.

Prioritizing Mobilization with Multicentric Castleman's Disease Superimposed on Incomplete Spinal Cord Injury: A Case Report

Prioritizing Mobilization with Multicentric Castleman's Disease Superimposed on Incomplete Spinal Cord Injury: A Case Report