Castleman's Disease Research Articles

Higher Rate of Relapse of KSHV/HHV-8 Associated Multicentric Castleman Disease after Rituximab Therapy in HIV- Patients Than in HIV+ Patients

KSHV/HHV-8 associated multicentric Castleman disease (HHV-8 MCD) is a rare lymphoproliferative disorder associating lymphadenopathy, splenomegaly, fever and inflammatory symptoms with high serum CRP, hypergammaglobulinemia and high plasma HHV-8 DNA viral load. HHV-8 MCD mainly affects HIV infected patients but can also be observed in HIV negative patients born in countries with high HHV-8 prevalence. We retrospectively analysed a cohort of 99 patients (73 HIV+ and 26 HIV-) with HHV-8 MCD treated with rituximab (off-label). The baseline characteristics were similar in HIV- and HIV+ patients although HIV- patients were older at MCD diagnosis (median, 65 vs 42 years) and presented less frequently with previous Kaposi sarcoma lesions (15% vs 40%). Out of these 99 patients, 95 patients (25 HIV- and 70 HIV+) achieved CR after a rituximab based therapy. After a median follow-up of 51 months (743 visits), 36 patients were considered as in treatment failure because of MCD relapse, KS progression, lymphoma or death. The 5-year progression-free survival (PFS) was 54,4 % [IC95% 40,8-66,0]. Relapse or progression of HHV-8 disease occured in 12 /25 (48%) HIV- patients and in 24 /75 (32%) HIV+ patients. The 5-year PFS was lower in HIV- patients than in HIV+ patients : 25,7 % [IC95% 5,2-53,6] and 61,6% [IC95% 46,2-73,7], respectively (p= 0.02 ). We have retrospectively analysed the kinetics of blood HHV-8 DNA, CD19+ B-cells and serum CRP after a first rituximab induced CR. The median times for a rise of plasma HHV-8 DNA above 3 logs/mL (n=57), CD19+ B-cells above 1/mm3 (n=59) and serum CRP above 20 mg/L (n=42) were 5,8 months [IQR 2,8-19,8], 8 months [IQR 4,7-13,4] and 13,1 months [IQR 3,4-27,8], respectively. The median time for treatment failure after such events were 4,5 months [IQR 0-16,4] for HHV8-DNA, 13,9 months [IQR 2,7-22,5] for CD19+ B-cells and 2 months [IQR 0-6,9] for CRP. These data show that in most patients, B cells became detectable again and that plasma HHV-8 DNA rose above 3 logs/mL during the first year post-rituximab and that these events could be followed by a rise in serum CRP preceding treatment failure. We suggest that these covariates should be monitored every 4-6 months although the decision of reintroducing specific therapy should still rely on the occurrence of clinical symptoms. The lower rate of relapse observed in the HIV+ population despite a longer follow-up period, may be due to a younger age and to the possible immune reconstitution upon antiretroviral therapy in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

LRG1, a Novel Serum Biomarker for Idiopathic Multicentric Castleman Disease Activity

Objective: To investigate the relationship between serum Leucine-Rich α-2-Glycoprotein-1 (LRG1) and idiopathic multicentric Castleman disease (iMCD) activity, and to verify the effectiveness of LRG1 in monitoring treatment response. Methods: Clinical data and serum samples were collected from iMCD patients in flare and remission state diagnosed between August 2015 and April 2022 in Peking Union Medical College Hospital. Enzyme-linked Immunosorbent Assay was performed to quantify LRG1 concentration, which was further analyzed with patients' clinical data. Results: 81 patients were included, with 10 cases of iMCD-TAFRO and 40 cases of severe-disease, and 110 serum samples were acquired. The average LRG1 concentration was 113.5±14.27μg/mL in 76 samples of disease flare, 47.48±14.23μg/mL in 16 biochemical PR, and 14.4±1.18μg/mL in 18 biochemical CR samples. The difference is significant among different disease states (Flare vs PR, p = 0.0019; Flare vs CR, p < 0.0001; PR vs CR, p = 0.0349). Paired sample of 20 cases showed significant decrease of serum LRG1 from Flare to PR/CR (-35.36±5.94μg/mL, p < 0.0001) after treatment (figure 1A). Serum LRG1 level was also elevated in those iMCD-TAFRO cases with normal serum CRP level during disease flare. Baseline LRG1 level was significantly higher in patients with severe disease (142.6±23.2μg/mL vs 81.2±14.0μg/mL, p = 0.0271), which could be identified efficiently by baseline LRG1 over 57.75μg/mL (AUC = 0.655, p = 0.0203, sensitivity 70%, specificity 63.89%). Among 38 patients using thalidomide-cyclophosphamide-prednisone (TCP) regimen as first-line treatment, the median time to next treatment in patients with baseline LRG1 over 57.75μg/mL was significantly shorter than those under 57.75μg/mL (10 vs 30 months, HR: 2.254, 95% CI: 1.052-4.828, p = 0.0277) (figure 1B). Conclusion: Serum LRG1 level could mirror disease activity, and could be utilized to monitor the treatment response, especially in iMCD-TAFRO subtype. Serum LRG1 level over 57.75μg/mL could efficiently identify patients with severe iMCD, and had the potential to predict the efficacy of TCP regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Idiopathic Multicentric Castleman Disease Interactive Disease Awareness and Educational Tool for Pathologists

Background: Idiopathic multicentric Castleman disease (iMCD) is a rare systemic lymphoproliferative disease that is challenging to diagnose. Diagnostic criteria require the identification of characteristic histopathology in the context of supportive clinical, radiologic, and serologic findings. However, the histologic features of iMCD can be subtle and nonspecific, which delays an accurate diagnosis. Timely diagnosis and early intervention are essential to reduce patient mortality. Developing a disease awareness and educational tool for pathologists may support the identification of future iMCD cases. Methods: International pathologists were identified to support the development of an interactive pathology tool for iMCD. To validate the tool, a selection of pathologists attended a virtual workshop to provide insight and help shape the content and format of the tool. Prior to workshop, attendees were asked to complete a 14-question survey on the diagnosis of iMCD, including exclusion of other diseases, conditions with similar histopathological features, and features specific to iMCD. Results: The educational tool is currently in development and takes into consideration the varied diagnostic journeys in different centers/countries. Histopathologic criteria for iMCD require evaluation of the degree of plasmacytosis, regressed germinal centers, follicular dendritic cell proliferation, vascular proliferation, and hyperplastic germinal centers. While the differences between high grade (grade 3) and normal (grade 0) findings are straightforward, differentiating grade 1 from grade 2 (the diagnostic cut-off) is challenging and subjective. The tool will focus on these diagnostic grey-zones to include points of differentiation between Grades 1 and 2 iMCD, disease exclusion criteria, and the use of diagnostic images that can be explored. Thus far, development of the tool has shown there is a need for standardized disease terminology between pathologists, that the use of template reports and language guidance may support the diagnostic process, and that patient case studies and the use of real-world examples support disease recognition. The educational tool is anticipated to be ready for release in September 2022. Conclusions: Diagnosis of iMCD is complex, and, despite the existence of well-established diagnostic criteria, pathological differentiation remains a challenge. Increasing awareness of iMCD-specifically the key diagnostic criteria-will assist with both timely diagnoses and the treatment of this disease.

Characteristics of Circulating KSHV-Infected Cells during Active KSHV+ Multicentric Castleman Disease

Characteristics of Circulating KSHV-Infected Cells during Active KSHV+ Multicentric Castleman Disease

Insights into the Natural History and Treatment Outcomes of Hemophagocytic Lymphohistiocytosis (HLH): The into-HLH Registry

Purpose: Hemophagocytic Lymphohistiocytosis (HLH) is a complex, hyperinflammatory syndrome resulting from the interplay of genetic predisposition and various environmental factors. In the last 25 years, scientific insights and treatments have evolved substantially with novel targeted therapies. However, approximately 30% of patients do not respond to therapy despite available treatment options. Thus, there is an unmet need for a deeper understanding of the natural history, clinical/ etiologic diversity, complications, and treatment outcomes of HLH patients, specifically from North America. Therefore, we established a robust registry to better understand the natural history, treatment patterns, and outcomes of HLH syndrome. Methods: To address these knowledge gaps, we established a non-interventional, observational study with a dual-enrollment method for maximum engagement (NCT05277272) modeled after the ACCELERATE Castleman disease natural history registry. Patients are consented and enrolled in the study via the traditional Physician Driven Arm (PDA) and a Patient-Powered Arm (PPA), in which patients are directly recruited through the Registry's website (www.hlhregistry.org). The Registry is a collaboration between Cincinnati Children's Hospital Medical Center (the academic sponsor), Texas Children's Hospital, The North American Consortium for Histiocytosis (NACHO), and Sobi Inc. (the industry sponsor). Anticipated enrollment is > 200 patients with clinically suspected or confirmed HLH, including familial and all other subtypes of HLH. Medical records are acquired and abstracted by the INTO-HLH Registry Team (IHRT) at Cincinnati Children's Hospital Medical Center into pre-specified electronic case report forms (eCRF). HLH-related data is abstracted from initial disease presentation to diagnosis, through treatment until Hematopoietic Stem Cell Transplantation (HSCT) or end of HLH-directed treatments. Patients are followed for at least five years to assess short- and long-term outcomes. Discrete HLH episodes are captured separately. Physicians at the PDA sites perform minimal data abstraction reflecting their subjective narrative regarding patients' treatments and responses. In addition, the patients are offered to answer optional patient-reported outcomes questionnaires and participate in correlative biology studies. The INTO-HLH steering committee adjudicates specific diagnoses and reviews adverse treatment events and causes of mortality. Results: Enrollment is ongoing with pediatric patients with familial HLH and adult patients with other subtypes of HLH already consented. The primary objective of the research is to describe the natural history of patients with HLH, and the secondary objective is to describe treatment patterns, responses, and outcomes. In addition, health-related quality of life, disease-related health burden, and the relationship between biologic variability and clinical outcomes will be assessed as exploratory objectives. Conclusion: The INTO-HLH Registry aims to advance clinical understanding and improve treatment outcomes in patients with HLH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A National, Multicenter, Retrospective Study of Castleman Disease Implementing Cdcn Criteria: 'severe Imcd' Is Indeed Severe

Objective: To delineate the distribution, clinical characteristics and prognostic features of different subtypes of Castleman disease based on the CDCN criteria. To describe the first-line treatment choice for iMCD in China before the era of IL-6-directed therapy. Methods: This was a national, observational, retrospective study which enrolled consecutive patients with CD diagnosed at 40 large Chinese institutions from 2000 to 2021. Patients were classified into different CD subtypes according to the CDCN criteria. The primary outcomes were the distribution of different CD subtypes, descriptions of demographic and clinical characteristics, treatment options and overall survival. Results: A total of 1634 CD patients (unicentric CD(UCD), n=903; multicentric CD(MCD), n=731) were enrolled. Among UCDs, hyaline-vascular (HV) was the major pathological subtype, and there were 162(17.9%) patients with an MCD-like inflammatory state (UCD-MIS). Among the MCD patients, there were 12 HHV-8-related MCD patients and 719 HHV-8-negative MCD patients (asymptomatic MCD (aMCD), n=139; iMCD, n=580). Of the 580 iMCD patients, 41(7.1%) were classified as having iMCD-TAFRO, while the others were classified as having iMCD-NOS. Among the iMCD patients with first-line treatment information, a trend from pulse combination chemotherapy toward a continuous approach was noticed (Fig 1A). Survival analysis revealed significant differences between different subtypes, and the estimated 3-year overall survival rates for UCD, iMCD-NOS and iMCD-TAFRO patients were 98.0%, 89.6% and 65.7%, respectively. Among the iMCD-NOS patients, the multivariate Cox regression model identified 'severe iMCD' (HR=4.540; 95% CI 1.888-10.915, p=0.001) as the only independent risk factor for death (Fig 1B). The estimated 3-year overall survival rates for severe and nonsevere iMCD-NOS patients were 93.8% and 75.6%, respectively. Conclusion: This study depicts a whole picture of CD subtype distribution, treatment options and survival information in China and validates the rationality of the concept of severe iMCD proposed by the CDCN. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunoglobulin G4-Related Disease (IgG4-RD) Mimicking Hyaline Vascular Castleman Disease

Abstract Introduction/Objective Immunoglobulin G4-related disease (IgG4-RD) is a newly emerging immune-mediated fibroinflammatory disease characterized by increased IgG-4+ plasma cells. In soft tissue and visceral organs, the IgG4+ plasma cells often accompany a storiform pattern of fibrosis with obliterative phlebitis. In lymph nodes, rare cases have been described in the literature mimicking Multicentric Castleman Disease. Methods/Case Report Herein, we present a case of a 59-year-old male with history of lung adenocarcinoma status post resection one year prior, who presented with several months of unintentional weight loss and worsening of cervical lymphadenopathy. CT scan of the neck demonstrated extensive cervical lymphadenopathy. Incidentally, patient had traveled to a foreign country and had a positive QuantiFERON result. Clinical suspicion was either nodal metastatic disease or TB infection. An excisional biopsy of the left cervical lymph node was performed. Microscopic examination revealed numerous hyperplastic follicles with significant hyaline deposition, concentrically thickened mantle zones, radially penetrating vessels, increased interfollicular vascularity and plasmacytosis; morphologic features commonly associated with Hyaline-Vascular Castleman Disease (HVCD). Additionally, plasmacytosis within germinal center was identified. Immunohistochemical stains demonstrated significant IgG4+ plasma cells (approaching 108/HPF) within the germinal centers. All plasma cells were polytypic. Results (if a Case Study enter NA) N/A. Conclusion Commonly described patterns for IgG4-RD in the literature are multicentric Castleman disease (MCD)-like, whereas, in our case, we present intrafollicular plasma cell proliferation pattern of IgG4-RD with classic background features of HVCD. Accurate diagnosis and distinction between these two entities is imperative for prognostication, treatment and clinical management of IgG4-RD.

Unicentric Castleman Disease: A Rare Diagnosis of Radiological and Histological Correlation.

Castleman disease is an uncommon nonneoplastic, lymphoproliferative disorder of that is associated with lymphadenopathy and nonclonal lymph nodes hyperplasia. It is further subdivided into two types: Unicentric Castleman disease and Multicentric Castleman disease. Unicentric Castleman disease is rare to be reported in patients having AIDS, because HIV infected patients most commonly presented with Multicentric Castleman disease and they mostly coinfected with HHV-8. Herein we reported a rare presentation of Unicentric Castleman disease with hyaline vascular variety evident Histopathologically as a preoperative diagnosis. The patient was initially managed conservatively and surgical excision (excisional biopsy) of the left cervical lymph node was than performed and sent for histopathology. The Immunohistochemistry findings were also consistent with the diagnosis of Castleman disease Hyaline vascular type as evident from left cervical lymph node excisional biopsy.

Membranoproliferative Glomerulonephritis (MPGN) in the Setting of Unicentric Castleman Disease

Membranoproliferative Glomerulonephritis (MPGN) in the Setting of Unicentric Castleman Disease

Primary sclerosing cholangitis-A long night's journey into day.

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Multicentric Castleman disease with trismus.

A 58-year-old man visited our hospital with trismus and anorexia in the past 1 month (Fig. 1A, B). Multicentric Castleman disease was suspected due to cervical and axillary lymphadenopathy on CT, a high inflammatory response and IL-6 level elevation. Lymph node biopsy revealed mantle zone development, interfollicular expansion, extensive plasma cell infiltration and cluster of differentiation 3-positive (CD3+) T cell accumulation, leading to the diagnosis of plasmacytic Castleman disease. CT findings could not explain the cause of trismus (Fig. 1C). PET-CT revealed increased fluorodeoxyglucose uptake in the right temporomandibular joint, implicating temporomandibular joint arthritis as the cause of trismus (Fig. 1D, arrow). Trismus rapidly improved after prednisolone and IL-6 inhibitor administration. Similar to RA, Castleman disease is a lymphoproliferative disease with IL-6–related systemic inflammation. Temporomandibular joint arthritis is an articular symptom of RA, but arthritis in Castleman disease has rarely been reported. Activation of CD3+ cells by IL-6 is a potential mechanism of arthritis [1]. CD3+ T cells were clearly observed in the lymph nodes in our patient, which indicates arthritis. We report a case of trismus associated with temporomandibular arthritis, which we consider to be highly representative of the pathophysiology of Castleman disease.

A novel approach for characterization of KSHV-associated multicentric Castleman disease from effusions.

A biopsy of lymphoid tissue is currently required to diagnose Kaposi sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD). Patients showing clinical manifestations of KSHV-MCD but no pathological changes of KSHV-MCD are diagnosed as KSHV inflammatory cytokine syndrome. However, a lymph node biopsy is not always feasible to make the distinction. A pathognomonic feature of lymph nodes in KSHV-MCD is the expansion of KSHV-infected, lambda-restricted but polyclonal plasmablasts. To investigate whether these cells also reside in extra-nodal sites, effusion from 11 patients with KSHV-MCD and 19 with KSHV inflammatory cytokine syndrome was analysed by multiparametric flow cytometry. A distinct, lambda-restricted plasmablastic population (LRP) with highly consistent immunophenotype was detected in effusions in 8/11 patients with KSHV-MCD. The same population was also observed in 7/19 patients with KSHV inflammatory cytokine syndrome. The detection of LRP stratified KSHV inflammatory cytokine syndrome into two clinically distinct subgroups; those with detectable LRP closely resembled KSHV-MCD, showing similar KSHV viral load, comparable severity of thrombocytopenia and hypoalbuminaemia, and similar incidences of hepatosplenomegaly. Collectively, the detection of LRP by flow cytometry can serve as a valuable tool in diagnosing KSHV-MCD. KSHV inflammatory cytokine syndrome with LRP in effusions may represent a liquid-form of KSHV-MCD.

HUMAN HERPESVIRUS 8 (HHV8)-NEGATIVE MULTICENTRIC CASTLEMAN DISEASE LEADING TO GROUP 1 PULMONARY ARTERY HYPERTENSION AND CLINICALLY SIGNIFICANT RIGHT VENTRICULAR SYSTOLIC DYSFUNCTION

HUMAN HERPESVIRUS 8 (HHV8)-NEGATIVE MULTICENTRIC CASTLEMAN DISEASE LEADING TO GROUP 1 PULMONARY ARTERY HYPERTENSION AND CLINICALLY SIGNIFICANT RIGHT VENTRICULAR SYSTOLIC DYSFUNCTION

IDIOPATHIC MULTICENTRIC CASTLEMAN DISEASE (IMCD) AS A MANIFESTATION OF POST-COVID-19 INFLAMMATORY SYNDROME

IDIOPATHIC MULTICENTRIC CASTLEMAN DISEASE (IMCD) AS A MANIFESTATION OF POST-COVID-19 INFLAMMATORY SYNDROME

La maladie de Castleman

The term "Castleman disease" covers a variety of entities that have very different clinical, biological, pathological and physiopathological features. In this issue, we review the characteristics of the unicentric Castleman disease, of the HHV8 associated multicentric Castleman disease and the idiopathic multicentric Castleman disease associated or not with TAFRO syndrome ("thrombocytopenia, anasarca, fever, reticulin myelofibrosis and/or renal insufficiency, organomegaly"). We detail the differential diagnostics of these entities.

Organ dysfunction, thrombotic events and malignancies in patients with idiopathic multicentric castleman disease: a population-level US health claims analysis

Organ dysfunction, thrombotic events and malignancies in patients with idiopathic multicentric castleman disease: a population-level US health claims analysis

Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease.

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.

Analysis of albumin as a prognostic factor in HHV-8/HIV-negative Castleman disease from a multicenter study

As a rare lymphoproliferative disorder, many patients with HHV-8/HIV-negative Castleman disease (CD) have hypoalbuminemia. However, data is limited on whether hypoalbuminemia is an independent predictor of CD. We retrospectively collected data from 230 patients diagnosed at 12 medical centers in China and the U.S. Different classifications included 147 patients with unicentric CD (UCD) and 83 with idiopathic multicentric CD (iMCD). Adjusted smooth curve fitting showed that the relationship between albumin and all-cause death of patients with CD and iMCD was linear. Cox proportional hazards regression modeling showed a negative association between the risk of death and albumin level (hazard ratio [HR]: 0.84; 95% CI, 0.76, 0.93). Using the Kaplan–Meier method, we determined that hypoproteinemia was a risk factor for poorer prognosis in patients with CD, UCD, and iMCD. Albumin was independently and negatively associated with the risk of death in CD patients, especially those with iMCD.

Lymphomas in People Living with HIV

Lymphomas in people living with HIV (PLWH) are associated with Epstein Barr virus (EBV) and Kaposi-sarcoma-associated herpesvirus (KSHV). They include primary effusion lymphoma, large B-cell lymphoma arising in multicentric Castleman disease, plasmablastic lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and Hodgkin lymphoma (HL). Inclusion of these lymphomas in the WHO classification of tumors of hematopoietic and lymphoid tissues and the increasing recognition of these disorders have resulted in established clinical management that has led to improved outcomes. In this review, we report on the current management in lymphomas occurring in PLWH with an emphasis on KSHV-associated disorders and EBV-related HL. We also report on the simultaneous occurrence of KSHV- and EBV-associated disorders and highlight preventive measures that have been planned for tumor prevention in PLWH. In conclusion, it is recommended that treatment choice for PLWH affected by lymphoma, and receiving effective combined antiretroviral therapy (cART), should not be influenced by HIV status. Moreover, there is an urgent need (1) to reduce the current large disparities in health care between HIV-infected and HIV-uninfected populations, (2) to disseminate effective treatment, and (3) to implement preventive strategies for PLWH.

Castleman disease of the parapharyngeal space: Diagnosis and management

IntroductionCastleman's disease (CD) is a rare and benign disease often identified in the mediastinum with few cases in the head and neck area. Parapharyngeal Castleman's disease was rarely reported in the literature.The aim of our work was to discuss the management of this particular location of CD. It was about a case report that has been reported in line with the SCARE 2020 criteria (Agha et al., 2020 [1]).Case presentationWe report the case of a 53-year-old female patient who presented a left parotid tumefaction. Radiological investigations showed a parapharyngeal mass that was surgically removed. Definitive pathologic report concluded to Castleman's disease. She presented, one year later, a retropharyngeal recurrence, which was treated by radiotherapy with good response.Clinical discussion and conclusionCastleman's disease located in parapharyngeal spaces is an entity that was rarely reported in the literature. Surgical excision is the golden standard treatment. Radiotherapy is also an effective treatment that can be offered for unresectable cases or recurrences of Castleman's disease.