Retrospective cohort evaluation of non-HIV Castleman disease from a single academic center in Beijing, China.

The purpose is to ascertain the clinical impact of Castleman disease (CD) by reassessment of the real-world data from Peking University First Hospital (PKUFH). The results will contribute to the standardization of diagnosis and treatment on CDs. Based on the last 15-year retrospective real-world data from Peking University First Hospital (PKUFH), we reclassified and re-evaluated the clinical and pathological information of patients with pathologically suspected diagnosis of CD. A total of 203 patients were included in our study, in which the diagnosis of CD was confirmed in 189 cases, including 118 patients with unicentric CD (UCD, n = 118, 62.4%) and 71 patients with multicentric CD (MCD, n = 71, 37.6%). A total of 44.1% (n = 52) of UCDs in our cohort were complicated with paraneoplastic pemphigus (PNP). The treatment of UCD is primarily surgical, with a 5-year overall survival (OS) of 88.1%. Patients with PNP had a poorer prognosis than those without PNP (82.9% (95% CI 123-178) vs 92.8% (95% CI 168-196), log-rank p = 0.041). The rate of concurrent systemic symptoms was 74.6% (n = 53), and renal involvement occurred in 49.3% (n = 35) MCD patients. The MCD treatments were mainly chemotherapy regimens, with a 5-year OS of 77.6% (95% CI, 143-213). Patients with UCD demonstrate a better overall prognosis than patients with MCD. But the prognosis of those complicated with PNP was poor. The differential diagnosis of MCD is extensive. MCD treatment in China is heterogeneous. The inaccessibility of anti-IL-6-targeted drugs in China may contribute to the poor prognosis for patients with MCD.A preprint has previously been published (Guo et al. 34).

Castleman disease- demographics, associations, and outcomes: an analysis of adult 791 cases.

BACKGROUND: Castleman disease (CD), also known as angiofollicular lymph node hyperplasia or large lymph node hyperplasia, is a rare medical condition. Despite its rarity, it exhibits diverse clinical presentations and outcomes, which pose challenges for comprehensive understanding and management. This study aims to shed light on the demographics, associations, and outcomes of CD by conducting a retrospective analysis. METHODS: The National Inpatient Sample (US) was used to identify patients with the diagnosis of Castleman disease using ICD-10 diagnosis code D47.Z2, during the years 2016-2019. Data was collected on demographics, associated diagnoses, treatments and outcomes. Data analysis was performed using STATA Version 17, College Station, TX: Stata Corp LLC. RESULTS: Our study identified 791 hospitalizations involving adult CD patients. The mean age of these patients was 52.4 years, with a male predominance (56.1%). Whites comprised the largest racial group affected (50.1%). Most patients were covered by Medicare (39.6%). The majority received treatment in urban teaching hospitals (84.0%) and large-bed size facilities (62.5%). In-hospital mortality was low at 2.8%, with an average length of stay of 7.5 days and average total charges of $109,308. Common associations included acute kidney injury (27.0%), congestive heart failure (17.1%), sepsis (16.4%), and acute respiratory failure (12.6%). Hematological and lymphatic associations featured anemia (47.5%), thrombocytopenia (12.2%), and other conditions. Red blood cell transfusions were administered to 11.1% of patients. CONCLUSION: This study contributes valuable insights into CD, a rare and clinically heterogeneous disease. It underscores the importance of recognizing its associations and complications. Additionally, it highlights the need for further research and improved diagnostic and treatment guidelines to address the complexity of this condition.

Comprehensive analysis of 65 patients with Castleman disease in a single center in China.

This study aimed to investigate the epidemiologic, clinical, pathological characteristics, and treatment of patients with Castleman disease (CD) in a single center in China. We retrospectively analyzed the data of 65 Chinese CD patients, divided into unicentric CD (UCD) and multicentric CD (MCD) groups, and also microscopic subtypes as hypervascular (HV), plasmacytic (PC) and Mixed. Based on whether HHV-8 infection existed, MCD was subdivided into HHV-8-associated MCD and idiopathic Castleman disease (iMCD). Detailed epidemiologic, clinicopathological, and treatment data were analyzed and discussed. Of total 65 patients (UCD 33, MCD 32), HV (81.8%) accounted for the most of UCD and total. More females in UCD (60.6%) and more males in MCD (65.6%) were observed. CD occurred in all age groups, most commonly in 40-49 years. The mean age of onset of total was 38.5 years with PC higher than HV (45.5 vs. 35.1 years, P = 0.0413). The median diagnosis delay of MCD was longer than that of UCD (3.00 vs. 1.25 months, P = 0.0436). Abdomen (39.4%) and neck (30.3%) were the most-seen locations of lymphadenopathy in UCD, with neck (65.6%) being predominant in MCD. Mean major diameter of specimens of UCD was greater than MCD (6.4 vs. 3.1 cm, P < 0.0001). These results provided the featured and detailed profile of Castleman disease in Henan province in China with a considerable number of cases, which presented distinct evidence with other studies.

Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6-directed therapy.

The epidemiology of human herpesvirus-8-negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood. Prior epidemiologic studies of CD and iMCD have been hampered by difficulties in accurate case ascertainment resulting from a lack of uniform diagnostic criteria and a disease-specific International Classification of Diseases (ICD) code. In this study, we provide reliable estimates of CD and iMCD in the United States using a novel claims-based algorithm that includes a CD-specific ICD (10th revision) diagnosis code (D47.Z2) supported by the presence of ≥2 claims codes corresponding to the minor criteria from the international evidence-based diagnostic criteria for iMCD. We additionally analyzed the treatment classes and patterns in the clinical course of patients with iMCD. Using an administrative claims database of 30.7 million individuals enrolled between 1 January 2017 and 31 December 2018, we identified 254 patients with iMCD, with an estimated annual incidence and prevalence of 3.4 (95% confidence interval [CI], 1.4-9.2) and 6.9 (95% CI, 3.7-13.3) cases per million, respectively. Among patients with iMCD, 39% received corticosteroid monotherapy, 33.1% received no iMCD-directed treatment, and 9.8% received interleukin-6 (IL-6)-targeted therapy with tocilizumab or siltuximab. Siltuximab, which is the only US Food and Drug Administration-approved treatment and established first-line treatment recommendation, was used in only 8.7% of patients with iMCD. This study provides the most up-to-date understanding of the iMCD disease burden in the United States and identifies a major unmet treatment need for IL-6-directed therapy in this vulnerable cohort.

[HHV-8 Related immunological and hematological diseases]. / Maladies immunologiques et hématologiques liées à HHV-8.

HHV-8 is an oncogenic Gammaherpesvirinae discovered in 1994 during the HIV pandemic. It is the causative agent of Kaposi's sarcoma, and is also associated with the occurrence of several aggressive B lymphoproliferative disorders. Most of them occur in an immunosuppression setting, usually due to HIV infection. Multicentric HHV8-associated Castleman's disease and KSHV Inflammatory Cytokine Syndrome (KICS) are primarily reactive entities with prominent systemic features. They illustrate the cytokinic storm induced by HHV-8 in its cell host. On the other hand, HHV-8 can drive proliferation and lymphomagenesis of its plasmablastic cell host, and is associated with a risk to develop aggressive lymphomas with plasmacytic differenciation. Primary effusion lymphoma usually localizes in body cavities and may affect other extra-nodal sites ; its prognostic is poor. Diffuse large B-cell lymphoma HHV-8, NOS affect more commonly nodes and blood and evolve from infected cell of HHV-8 associated Castleman disease. On the contrary, germinotropic lymphoproliferative disorders presents mainly as localized adenopathy with indolent course, and show polyclonality. Histology plays a key role in distinguishing these different entities and need expert reviewing, especially since they may be associated with each other. Besides lymphoproliferative disorders, HHV8 is associated with various hematological manifestations. The aim of this review is to provide an update on the presentation, diagnosis, and management of immunologic and hematologic complications associated with HHV-8.

Maladies de Castleman : épidémiologie, classification et critères diagnostiques.

Castleman disease is a group of rare disorders characterized by lymph node enlargement, specific microscopic changes to the lymph nodes, and a broad range of symptoms and laboratory findings. The two main subtypes are unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). The multicentric subtype can be further classified into two categories: HHV-8 positive multicentric Castleman disease and idiopathic multicentric Castleman disease (iMCD). In the United States (US), the annual incidence of Castleman disease (CD) has been estimated to range from 6500 to 7700 in a 2014 study. Approximately 75 percent were estimated to be unicentric CD and the remaining 25 percent were estimated to be split between HHV-8-associated MCD or HHV-8-negative/idiopathic MCD. Diagnostic criteria for iMCD have been established by an international working group of pediatric and adult pathology and clinical experts. The proposed consensus criteria require characteristic histopathologic findings on lymph node biopsy, enlargement of multiple lymph node regions, the presence of multiple clinical and laboratory abnormalities, and the exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. © 2022 Published by Elsevier Masson SAS on behalf of Société nationale française de médecine interne (SNFMI).

Patient's age and D-dimer levels predict the prognosis in patients with TAFRO syndrome.

OBJECTIVES: To identify prognostic factors for TAFRO syndrome, a rare inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. METHODS: Data of patients with TAFRO syndrome were extracted from a Japanese patient registry. Patients were divided into groups according to the clinical and laboratory parameters at initial presentation. Cut-off values for the laboratory parameters were determined using receiver operating characteristic curve analysis and by clinical relevance. Patient survival was analyzed by the Kaplan-Meier method. Univariable analysis was performed using log-rank tests. Multivariable analyses were performed with the logistic regression model and the Cox proportional hazards model. RESULTS: We extracted the data of 83 patients with TAFRO syndrome from the registry. Univariable analysis identified several potential prognostic factors. Of these factors, age ≥60 years and D-dimer ≥18 µg/dL remained significant predictors of poor overall survival in the multivariable Cox proportional hazards model. Based on these results, we developed a simple prognostic scoring system for TAFRO syndrome (TS-PSS). CONCLUSION: Patients in our cohort were stratified into low, intermediate, and high-risk groups by the TS-PSS. This system should be verified with independent patient cohorts in future studies.

Epidemiological analysis of multicentric and unicentric Castleman disease and TAFRO syndrome in Japan.

Castleman disease is a polyclonal lymphoproliferative disease which is clinically classified into unicentric (UCD) and multicentric (MCD). TAFRO syndrome is a relatively new concept that partly overlaps with MCD. Due to their rarity, their incidence remains unknown. This study investigated the incidence and prevalence of UCD, MCD, and TAFRO syndrome in Japan using a fixed-point observation method based on their incidence in Ishikawa prefecture. The annual incidences of MCD, UCD, and TAFRO syndrome in Japan were 309-731, 71-542, and 110-502, respectively, yielding annual incidence rates per million individuals of 2.4-5.8, 0.6-4.3, and 0.9-4.9, respectively, and nationwide prevalence of 4,180-14,900, 1,350-10,300, and 860-7,240, respectively. In conclusion, MCD, UCD and TAFRO syndrome may not be as rare as previously estimated in Japan.

Epidemiology of Castleman disease associated with AA amyloidosis: description of 2 new cases and literature review.

Introduction: HHV8-negative Castleman disease (CD) is classified as hyaline vascular (HV) type, or mixed or plasma cell (PC) types. It may present as multicentric CD (MCD) or unicentric CD (UCD). CD is a rare cause of AA amyloidosis (AAA). We aimed to report the main features of CD with secondary AAA through a description of new cases and a systematic literature review. Patients and methods: New cases were identified from the French National Reference Center for AAA. A systematic literature review was performed to identify HHV8-negative CD cases associated with AAA. Results: Thirty-seven patients were analysed, consisting of two new cases and 35 from literature. Twenty-three had UCD and 14 had MCD. PC was the main histologic subtype (n = 25; 68%) in both UCD and MCD patients. Surgical excision of UCD was performed in 21 patients (91%) with a favourable outcome, except for four patients (19%). Clinical and biologic remission was achieved in six patients with MCD (43%), all of whom were treated with anti-interleukin-6 (IL-6) therapy. Conclusions: AAA is a rare complication of CD, namely idiopathic MCD and UCD presenting with the PC histologic subtype. Surgical excision of UCD should be the first-line treatment whenever possible, while anti-IL-6 therapies seem effective for MCD.

Rare diseases that mimic Systemic Lupus Erythematosus (Lupus mimickers).

Several conditions have clinical and laboratory features that can mimic those present in Systemic Lupus Erythematosus (SLE). Some of these "SLE mimickers" are very common, such as rosacea which can be mistaken for the butterfly rash, while others such as Kikuchi disease, type-1 interferonopathies, Castleman's disease, prolidase deficiency, angioimmunoblastic T-cell lymphoma, Evans' syndrome in the context of primary immune deficiencies and the autoimmune lymphoproliferative syndrome are exceptionally uncommon. A proper diagnosis of SLE must therefore be based upon a complete medical history as well as on the adequate constellation of clinical or laboratory findings. While there is no single test that determines whether a patient has lupus or not, the search for auto-antibodies towards nuclear antigens is a key step in the diagnosis strategy, keeping in mind that ANAs are not specific for SLE. In case of persistent doubt, patients should be referred to reference centers with experience in the management of the disease.

Hiperplasia linfoide ileo-colónica en pacientes pediátricos / Ileo-colonic lymphoid hyperplasia in pediatric patients

Introducción: La Hiperplasia nodular linfoide gastrointestinal constituye una entidad infrecuente con manifestaciones clínicas diversas y con mayor frecuencia en la edad pediátrica. Objetivo: Caracterizar clínica, endoscópica e histológicamente a los pacientes pediátricos con hiperplasia linfoide de colon e íleon terminal diagnosticados en el Instituto de Gastroenterología. Material y Métodos: Se realizó un estudio descriptivo, transversal, en el periodo comprendido entre 2014 y 2016 en el Instituto de Gastroenterología. La muestra estuvo constituida por 50 pacientes, quienes cumplieron los criterios de inclusión y exclusión. Se evaluaron variables demográficas, clínicas, endoscópicas e histológicas, así como el comportamiento de la comorbilidad con enfermedades malignas, enfermedades inflamatorias intestinales, giardiosis, trastornos de la respuesta inmunohumoral y alergias alimentarias. Resultados: El sexo masculino, entre 7-10 años y el color de la piel blanca fueron los más frecuentes. El sangrado rectal fue el síntoma principal (62 por ciento) y la localización a nivel del íleon terminal en 69 por ciento, no se relacionó con enfermedad maligna, hubo tres pacientes con diagnóstico de hiperplasia linfoide de íleon terminal y colitis ulcerosa. El 74 por ciento presentó aspecto nodular por histología y 60 por ciento se le diagnosticó Giardia lamblia, en la evaluación inmunohumoral predominó los pacientes sin inmunocompromiso (78 por ciento), el Prick Test fue positivo en 60 por ciento, sobre todo, a la leche de vaca. Conclusiones: La manifestación clínica que predominó fue el sangrado rectal, endoscópicamente la localización en íleon y la forma nodular por histología. No encontramos comorbilidades con enfermedades malignas y fueron más frecuentes los trastornos alérgicos y parasitarios que las alteraciones inmunológicas(AU)

Introduction: Lymphoid nodular hyperplasia of the gastrointestinal tract is an uncommon entity with diverse clinical manifestations, which is more frequent in the pediatric age. Objective: To characterize clinically, endoscopically, and histologically, those pediatric patients with lymphoid hyperplasia of the colon and terminal ileum diagnosed in the Institute of Gastroenterology. Material and Methods: A descriptive, cross-sectional study was carried out during the period between 2014 and 2016 in the Institute of Gastroenterology. The sample consisted of 50 patients who met the inclusion and exclusion criteria. Demographic, clinical, endoscopic and histological variables were evaluated, as well as the behavior of comorbidity with malignant diseases, inflammatory bowel diseases, giardiasis, disorders of the humoral immune response and food allergies. Results: The male sex, the age group between 7-10 years, and the white skin color were the most frequent. Rectal bleeding was the main symptom (62 percent), and the location of the lesions in the terminal ileum was observed in 69 percent of the patients. There was no relationship between lymphoid hyperplasia and malignant disease, but three patients were diagnosed with lymphoid hyperplasia of the terminal ileum, and ulcerative colitis. 74 percent of the biopsies presented a nodular variety, and 60 percent of the patients were diagnosed with Giardia lamblia; the cases that were not immunocompromised prevailed in the evaluation of humoral immune response (78 percent); the Prick Test was positive in 60 percent of children, especially to cow's milk. Conclusions: The predominant clinical manifestation was rectal bleeding; the localization was in the ileum, which was seen by endoscopic procedure; and the nodular form was demonstrated by histology. We did not find comorbidities with malignant diseases, and allergic and parasitic disorders were more frequently diagnosed than immunological alterations(AU)

Effectiveness of rituximab-containing treatment regimens in idiopathic multicentric Castleman disease.

Human herpes virus type 8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disease often involving constitutional symptoms, cytopenias, and multiple organ system dysfunction. In China, the majority of MCD cases are HHV-8 negative. Given that siltuximab, the only FDA-approved treatment for iMCD is not available in China; rituximab- and cyclophosphamide-containing regimens are often used in the treatment of Chinese iMCD patients. To evaluate the efficacy of rituximab in this rare and heterogeneous disease, clinical and pathological data from 27 cases of iMCD were retrospectively analyzed from two large medical centers in China. The novel diagnostic criteria for iMCD were applied, and POEMS syndrome, IgG4-related diseases, and follicular dendritic cell sarcomas cases were excluded from analyses. Total response rate of rituximab- and cyclophosphamide-containing regimens was 55.5%, with 33.3% (9/27) of the cases reaching CR and 22.2% (6/27) PR. In the 14 cases of R-R iMCD, total response rate was only 42.9% (CR 14.3% [2/14], PR 28.6% [4/14]). The 5-year OS of these 27 iMCD cases was 81% (95% CI 64-98; 27 total patients, 4 events, 23 censored) after receiving these regimens, but the 5-year PFS was 43% (95% CI 19-66; 25 total patients, 11 events, 14 censored). Thus, rituximab-based regimens should be considered for the treatment of iMCD patients when siltuximab is not available and potentially in siltuximab-refractory cases.

The Clinical and Immunologic Features of Patients With Combined Anti-GBM Disease and Castleman Disease.

Patients with both anti-glomerular basement membrane (anti-GBM) disease and Castleman disease have been rarely reported. In this study, we report 3 patients with this combination. They had immunologic features similar to patients with classic anti-GBM disease. Sera from the 3 patients recognized the noncollagenous (NC) domain of the α3 chain of type IV collagen (α3(IV)NC1) and its 2 major epitopes, EA and EB. All 4 immunogloblin G (IgG) subclasses against α3(IV)NC1 were detectable, with predominance of IgG1. In one patient with lymph node biopsy specimens available, sporadic plasma cells producing α3(IV)NC1-IgG were found, suggesting a causal relationship between the 2 diseases. One patient, who achieved remission with antibody clearance and normalization of serum creatinine and interleukin 6 concentrations after plasma exchange and 3 cycles of chemotherapy, experienced recurrence of anti-GBM antibodies and an increase in interleukin 6 concentration after chemotherapy discontinuation because of adverse effects, but both returned to normal after another cycle of chemotherapy. This clinical course and the pathologic findings support the hypothesis that the Castleman disease-associated tumor cells are the source of the anti-GBM autoantibodies.

High proportion of TAFRO syndrome in Thai adult Castleman's disease patients: a 10-year experience.

Castleman's disease (CD) is a rare lymphoproliferative disorder, and its prevalence in Thailand is not known. This 10-year period study investigated the prevalence of CD in Thailand, and the clinical characteristics and outcomes of Thai CD patients, with special focus on the existence and prevalence of TAFRO syndrome. TAFRO syndrome is defined as CD with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. Thirty-three CD patients diagnosed and treated at Siriraj Hospital during January 2007 to December 2016 were included. The prevalence of CD was 1.4 per 1,000,000 patients/10 years. Median age was 46 years, with slight female predominance. Six patients were assigned to the TAFRO group. A high proportion of TAFRO syndrome (18.2%) was found among Thai adult CD patients. In addition to routine TAFRO diagnostic criteria, significantly lower hemoglobin and albumin levels were observed in the TAFRO group than in the non-TAFRO group. Treatment outcomes of CD patients were complete remission (52%), stable disease (30%), and death (13%). Three-year overall survival in the non-TAFRO group and TAFRO group was 88 and 50%, respectively. While most CD patients had a good prognosis, severe cases with TAFRO syndrome had poor outcome.

Comprehensive analysis of 225 Castleman's diseases in the oral maxillofacial and neck region: a rare disease revisited.

OBJECTIVES: The aim of the present study was to comprehensively summarize the epidemiological, clinicopathological characteristics, treatments as well as prognosis of Castleman's disease (CD) identified in the oral maxillofacial and neck region. MATERIALS AND METHODS: Patients with CD in the oral maxillofacial and neck were retrieved from disease registry at our institution from Jan. 1990 to Dec. 2015. Systematic reviews from both English and Chinese literature were performed to collect the detailed information about the oral maxillofacial and neck CD. The epidemiological, clinicopathological data and treatment outcomes were further statistically analyzed. RESULTS: Four patients with the oral maxillofacial and neck CD were identified and histologically confirmed as hyaline-vascular type. They underwent surgical excision without recurrence during the follow-up. Systematic literature reviews identified 221 cases from 123 eligible articles which satisfied the inclusion criteria. In 225 patients, most patients were diagnosed as unicentric (207) or hyaline-vascular type (205) of CD and identified in the neck, and treated by surgical resection with good prognosis. In contrast, the minority of patients was multicentric or plasma-cell/mixed type and treated by chemotherapy with inferior outcomes. Kaplan-Meir analyses revealed that both clinical and pathological types were significantly associated with patients' overall survival. CONCLUSIONS: Although rare, most cases of the oral maxillofacial neck CD are found in adults and classified as unicentric and hyaline-vascular type of CD. Complete surgical excision is preferred with favorable prognosis for unicentric disease, whereas chemotherapy is usually exploited for multicentric disease with inferior outcomes. CLINICAL RELEVANCE: These data provide comprehensive information about the epidemiology, clinicopathological features, treatments, and outcomes of the oral maxillofacial and neck CD.

Epidemiology of Castleman Disease.

Castleman disease is a rare entity, including unicentric Castleman disease (UCD), human herpesvirus-8 plus Castleman disease (HHV-8+MCD), and idiopathic multicentric Castleman disease (iMCD). UCD is the most common at 16 per million person years and occurs at every age. HHV-8+MCD incidence varies widely, mostly affecting human immunodeficiency virus-positive men. iMCD is likely a more heterogeneous disease with an estimated incidence of 5 per million person years. Improved definitions should improve understanding of the epidemiology of Castleman disease and its subtypes.

Kaposi's Sarcoma-Associated Herpesvirus: Epidemiology and Molecular Biology.

Kaposi's sarcoma-associated herpesvirus (KSHV), also known as Human herpesvirus 8 (HHV-8), is a member of the lymphotropic gammaherpesvirus subfamily and a human oncogenic virus. Since its discovery in AIDS-associated KS tissues by Drs. Yuan Chang and Patrick Moore, much progress has been made in the past two decades. There are four types of KS including classic KS, endemic KS, immunosuppressive therapy-related KS, and AIDS-associated KS. In addition to KS, KSHV is also involved in the development of primary effusion lymphoma (PEL) and certain types of multicentric Castleman's disease. KSHV manipulates numerous viral proteins to promote the progression of angiogenesis and tumorigenesis. In this chapter, we review the epidemiology and molecular biology of KSHV and the mechanisms underlying KSHV-induced diseases.