Treatment consistent with idiopathic multicentric Castleman disease guidelines is associated with improved outcomes.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with an unknown etiology. Clinical presentation is heterogeneous, ranging from mild constitutional symptoms with lymphadenopathy to life-threatening multiorgan dysfunction. International, consensus treatment guidelines developed in 2018 relied upon a limited number of clinical trials and small case series; however, to our knowledge, real-world performance of these recommendations has not been subsequently studied. Siltuximab, a monoclonal antibody against interleukin 6 (IL6), is approved for the treatment of iMCD and recommended first-line, and tocilizumab, a monoclonal antibody directed against the IL6 receptor, is recommended when siltuximab is unavailable. Chemotherapy, rituximab, and immunomodulators are recommended as second- and third-line treatments based on limited evidence. Corticosteroid monotherapy is used by clinicians, although not recommended. Here, we draw upon the ACCELERATE Natural History Registry to inventory regimens and evaluate regimen response for 102 expert-confirmed iMCD cases. Siltuximab with/without (w/wo) corticosteroids was associated with a 52% response, whereas corticosteroid monotherapy was associated with a 3% response. Anti-IL6-directed therapy with siltuximab or tocilizumab demonstrated better response and more durability than was observed with rituximab w/wo corticosteroids. Cytotoxic chemotherapy was associated with a 52% response and was predominantly administered in patients characterized by thrombocytopenia, anasarca, fever, renal failure/reticulin fibrosis, and organomegaly. Our results provide evidence in support of current recommendations to administer anti-IL6 as first-line treatment, to administer cytotoxic chemotherapy in patients with severe refractory disease, and to limit corticosteroid monotherapy. Evidence remains limited for effective agents for patients who are refractory to anti-IL6-directed therapy. This trial was registered at www.clinicaltrials.gov as #NCT02817997.

[Multicentric Castleman disease and tuberculosis in HIV positive patient]. / Enfermedad de Castleman multicéntrica y tuberculosis diseminada en paciente HIV positivo.

We present the case of a 40-year-old man, HIV positive with regular adherence to treatment, who consulted for intermittent febrile episodes during a two-years period, progressive diffuse abdominal pain and painless generalized lymphadenopathy in the last two months. Laboratory analysis showed pancytopenia, altered coagulation tests, hypoalbuminemia, and increased acute phase reactants. Computed tomography (CT) of the chest, abdomen and pelvis revealed hepato-splenomegaly and generalized lymphadenopathy. Multiple microbiological tests were performed, including cultures for Mycobacterium sp. from different samples, with negative results, except for the RT-PCR for HHV-8. An excisional biopsy of the left iliac lymph node was taken with findings compatible with Castleman's disease. Despite restarting antiretroviral therapy, the symptoms progressed, starting treatment with steroids and ganciclovir. After a week, he developed multiple organ failure and anasarca, which contraindicated the drugs previously started. A new CT of the chest showed infiltrates with a tree-in-bud pattern in the right upper lobe with bilateral pleural effusion, and at the abdominal level, progression of hepatosplenomegaly and ascites. He was transferred to the intensive care unit 48 hours later due to fulminant hepatic failure. The patient died within a few hours. Postmortem recieved culture results of the tracheal aspirate were positive for tuberculosis (TB) and the histopathology of the liver biopsy showed non-necrotizing granulomas. Our objective is to highlight the importance of screening for active TB, in our country, when Castleman's disease is suspected, before starting treatment, and to stand out that TB can also present as an infectious complication, increasing morbidity and mortality.

Presentamos el caso de un hombre de 40 años, HIV positivo con regular adherencia al tratamiento, que consultó por episodios febriles intermitentes de dos años de evolución, agregando en los últimos dos meses dolor abdominal difuso progresivo y adenomegalias generalizadas indoloras. En el laboratorio presentó pancitopenia, coagulopatía, hipoalbuminemia y reactantes de fase aguda aumentados. La tomografía computarizada (TC) de tórax, abdomen y pelvis únicamente evidenció hepato-esplenomegalia y adenomegalias generalizadas. Se realizaron múltiples exámenes microbiológicos, incluyendo cultivos para Mycobacterium sp. de distintas muestras, todos con resultados negativos, a excepción de la RT-PCR para VHH-8. Se tomó biopsia escisional de ganglio iliaco izquierdo con hallazgos compatibles con enfermedad de Castleman. A pesar de reiniciar terapia antirretroviral, la sintomatología progresó, iniciando tratamiento con corticoides y ganciclovir. Luego de una semana, desarrolló falla mulitorgánica y anasarca, que contraindicaron los fármacos iniciados. Se realizó nueva TC de tórax que mostró infiltrados con patrón en árbol en brote en lóbulo superior derecho asociado a derrame pleural bilateral, y a nivel abdominal, progresión de hepato-esplenomegalia y ascitis. Pasó a unidad de cuidados intensivos 48 horas después por falla hepática fulminante. El paciente falleció en pocas horas. Se recibió postmortem el cultivo del aspirado traqueal positivo para Mycobacterium tuberculosis y la punción-biopsia hepática con granulomas no necrotizantes. Nuestro objetivo es remarcar la importancia de pesquisar tuberculosis activa en nuestro país frente a la sospecha de enfermedad de Castleman antes de iniciar tratamiento, y resaltar que la TBC también puede presentarse como complicación infecciosa elevando la morbimortalidad.

Clinical and histopathology characteristics of Castleman disease: a multicenter study of 51 Brazilian patients.

Castleman's disease (CD) is a rare and heterogeneous lymphoproliferative disorder, with limited available clinical information in Brazil. A retrospective study was carried out through information contained in the medical records of 51 patients, between July 1999 and June 2020. Seven patients were excluded, and 44 were analyzed in total. The average age of unicentric CD (UCD) patients was 35 years old and of multicentric CD (MCD) patients was 49 years old (p = 0.013). Regarding gender, there was a predominance of females among patients with UCD (68.4%) and males in patients with MCD (57.9%) (p = 0.103). The most common site of involvement in UCD was the cervical region (36.8%). A total of 73.7% of patients with UCD and 68.4% of patients with MCD presented the histological form hialyne-vascular (HV) (p = 0.499). Most patients with laboratory abnormalities had MCD. A total of 78% of the patients were asymptomatic, with the majority of symptomatic patients with MCD (p = 0.042). Only two of the 27 patients evaluated for the presence of human immunodeficiency virus (HIV) had positive serology. HHV-8 was evaluated in 14 cases, being positive in two. Of the patients with UCD, 94.7% underwent excisional biopsy, against only 41.2% of patients with MCD (p = 0.01). The mean follow-up was 61 months. We observed similarities in the clinical profile between patients in our study and patients described in the literature, such as gender, mean age, B symptoms, visceromegaly, fluid accumulation, and treatment. Unlike the literature, the cervical region was the most affected site, besides the greater association of the HV histological subtype among patients with MCD.

International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Synchronous Unicentric Castleman Disease and Inflammatory Hepatocellular Adenoma: a Case Report.

Systemic symptoms such as fever and fatigue are non-specific manifestations spanning from inflammation to neoplasia. Here we report the case of a 34 year-old man who presented with systemic symptoms for four months. CT-scan and MRI revealed a 3.4 cm arterialized hepatic lesion and a 7 cm paraduodenal mass. Surgical resection of both lesions and histological examination revealed an inflammatory hepatocellular adenoma and a unicentric plasma cell type of Castleman disease. Moreover, a diffuse AA amyloid deposition in the liver was observed. Resection of both lesions was associated with an improvement of the symptoms. To our knowledge, this is the first report of a synchronous presentation of a unicentric plasma cell type of Castleman disease, inflammatory hepatocellular adenoma and AA amyloidosis.

Idiopathic multicentric Castleman's disease, infrequent cause of Lupus-like: case report

Castleman's disease (CD) or angiofollicular lymph node hyperplasia includes a heterogeneous mix of reactive lymphoproliferative processes with well-defined histological features. However, they differ in their localization patterns, clinical expression and etiopathogenesis. There are 4 types, one of them is the multicentric CD that is not associated with any viruses and has re-cently been called idiopathic MCD (iMCD). iMCD is a lymphoproliferative disorder with specific histopathological characteristics, more than one region of affected lymph nodes and absence of infection associated to human herpesvirus 8 and human immunodeficiency virus (HIV). iMCD covers multiple differential diagnoses and might simulate autoimmune diseases such as syste-mic lupus erythematosus. The aim of this article is to report the case of a patient with Castle-man's disease and lupus-like presentation. We present the case of a 38-year-old man without morbid history, who presented lumbago, fever, diaphoresis and asthenia with two months of evolution, associated to bilateral cervical adenopathies. General examinations result negative, antinuclear antibodies at a dilution of 1/640 were positive, and extractable nuclear antigens were positive suggesting moderate Systemic Lupus Erythematosus (SLE) plus secondary Sjö-gren's. Methylprednisolone and Hydroxycloroquine boli were thus initiated. The patient evolved with anasarca, severe anemia, acidosis, polyserositis and multiple mediastinal adenopathies. Immunoglobulin and cyclophosphamide were thus initiated. He later presented fever, throm-bocytopenia and nephrotic syndrome. Biopsy of cervical lymph node reported lymphadenitis with polyclonal plasmacytosis and concentric lymphoid hyperplasia, in agreement with iMCD. Treatment with Rituximab was initiated, which led to the favorable evolution of the patient. iMCD is a systemic inflammatory disease, its presentation corresponds to a constitutional syndrome resulting in a wide differential diagnosis. Every time suspicious adenopathies appear, they must be biopsied since this might lead to a definitive diagnosis

Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.

Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.

Calcified fibrous pseudotumor with Castleman disease

Simultaneous calcified fibrous pseudotumor (CFT) and Castleman disease (CD) is an extremely rare association. CD is an uncommon lymphoproliferative disease that can arise in various sites of the body, while CFT is a rare type of benign fibrous lesion that frequently affects children and young adults, occurring as solitary or multiple lesions throughout the human body. Both entities are rare and exhibit typical and diverse histomorphological features. We report the case of a 15-year-old female patient, who, at the age of 13 had a biopsy performed at an external medical center; however, after 4 months the lesion had regrown. This lesion was removed with a surgical operation; however, it regrew 2 years later and was removed a third time. The results of the latter two biopsies were the same: CFT accompanying CD. The histologic examination of the excised lymph node and the surrounding tissue showed hyalinized fibrous tissue containing dystrophic and psammomatous calcification. In this case, the hyaline vascular type of CD was found to be intertwined with a CFT, which hampered the differentiation of whether both entities emerged within the lymph node or if the CFT developed from the soft tissue and then involved the lymph node. Future studies involving larger case series will provide a more precise insight, which should serve to resolve the current uncertainty.

Multicentric Castleman's disease in human immunodeficiency virus infection: two case reports.

BACKGROUND: Castleman's Disease is a rare B-cell lymphoproliferative disease. It is mostly benign and is characterized by non-neoplastic lymph node hypertrophy, associated with infection by human herpesvirus-8 in people with the human immunodeficiency virus/acquired immunodeficiency syndrome. Although the unicentric or localized form presents as benign, the multifocal form can manifest severe systemic symptoms. We report two unusual cases of men presenting cervical enlarged lymph nodes that were believed to be infectious. CASE PRESENTATION: The first case is a 41-year-old feoderm man who presented to the Department of Infectious Diseases of the Hospital das Clínicas in May 2015, with irregular fever history (38-39 °C), dyspnea, weight loss (8 kg/1 year), and asthenia with increased cervical lymph nodes of 1-year duration. His immunohistochemical diagnosis presented Castleman's disease in plasmacytic/diffuse form. In the second case, a 35-year-old feoderm man presented at the same hospital with multiple cervical enlarged lymph nodes and histopathological evidence of Castleman's disease associated with human herpesvirus-8. CONCLUSION: Considering the importance of differential diagnosis of lymphoid disorders, Castleman's disease is a challenging diagnosis in people living with human immunodeficiency virus/acquired immunodeficiency syndrome and can be easily misdiagnosed when lymphoid disorders are present in the human immunodeficiency virus/acquired immunodeficiency syndrome population due to nonspecific symptoms and signs.

Castleman disease. Histopathological and immunohistochemical analysis of 39 cases. / Enfermedad de Castleman. Análisis histopatológico e inmunohistoquímico de treinta y nueve casos.

Introduction: Castleman disease (CD) is a rare lymphoproliferative that comprises two distinct clinical subtypes (unicentric and multicentric) and has two basic histopathology patterns that are hyaline-vascular (HV) and plasma-cell (PC) type. Some cases of multicentric PC disease are associated with HHV-8 infection. Objective: To present the histopathologic and immunohistochemical characteristics of 39 cases of CD. Methods: A review of cases with the diagnosis CD from the files of the Department of Pathology of the ABC Medical Centre in Mexico City was performed. Thirty-nine cases of CD were identified, and a detailed paraffin immunophenotypic study of 9 of them was completed using desmin, cytokeratin OSCAR (CO) and Epidermal growth factor receptor (EGFR), to evaluate the dendritic cell population. Results and Conclusions: Of the 39 cases of CD, 24 were HV and 15 CP. All HV cases were unicentric and only one case of CP was multicentric. The most frequent localization in both subtypes was in lymph nodes; 21/24 cases in HV and 15 cases of CP. All cases were immunostained with CD20 that was expressed in the germinal centers (CGs), CD3 in the paracortical zone, and CD21 in follicular dendritic cells (CDF) within CGs, with expansion towards the area of the hyperplastic mantle zone (only in the HV variant). One case of CD CP was positive for HHV-8. Of the nine cases (6 HV and 3 PC cases) that were detailed with IHC, we found EGFR expression in FDC in all but one of the 9 cases studied and desmin was positive in fibroblastic reticulum cells (FRC) in all, but one of the cases of CD. CO was positive FRC in 3 of 6 cases of HV type and all (3) of the PC type. Clinical, histopathological and HIV and HHV-8 status markers, allow for the classification of CD into groups with markedly different outcomes and disease associations.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

[Hyaline-vascular Multicentric Castleman's Disease in an immunocompetent patient]. / Enfermedad de Castleman Multicéntrica tipo hialino-vascular en paciente inmunocompetente.

A previously healthy, immunocompetent 67-year-old female presented with a one-month history of general symptoms, weight loss, night fevers, and bilateral lower extremity edema. On admission she had severe anemia, acute kidney injury, and multiple lymphadenopathies. An excisional biopsy of one of the axillary lymphadenopathies confirmed hyaline-vascular Castleman's disease. This rare disease is a polyclonal lymphoproliferative disorder that affects the normal lymph node architecture. According to its location it can be divided in unicentric (localized) or multicentric disease; it can be further divided according to histopathology in hyaline-vascular or plasmatic cells variety. Clinical presentation relates more to histopathological variety than to centricity. Human herpes virus 8 is ubiquitous in this disease and, along with interleukin 6, plays an important role in pathogenesis and symptoms presentation. Surgery is the go-to treatment of localized disease, while systemic chemotherapy is the option in multicentric disease. Communication between the clinical and anatomopathological teams is crucial; lag in diagnosis can lead to futile investigations in search of other diseases and delay in treatment.

Case Report Unicentric Castleman disease located in the anterior mediastinum misdiagnosed as invasive thymoma: a case report.

Castleman disease is a rare lymphoproliferative disorder of unknown etiology. The localized form, which usually presents as a slow-growing mass, is most commonly located in the mediastinum. Invasion of the vena anonyma by a mass has rarely been reported. We herein describe a case of initially misdiagnosed invasive thymoma in a 72-year-old woman, but postoperatively proven to have anterior mediastinal Castleman disease with invasion of the vena anonyma.

Enfermedad de Castleman e infección por HIV. Presentación de dos casos y revisión de la literatura / Castleman disease and HIV infection. Presentation of two cases and revision of the literature

La enfermedad de Castleman es un desorden linfoprolifera-tivo de origen aún incierto pero, en principio, relacionado con una dis-función de las células dendríticas foliculares y con una producción al-terada de distintas citoquinas, la mayor parte de ellas con actividad proinflamatoria y responsable de la sintomatología que presentan los pacientes.La relación con la presencia del HHV8, especialmente de las formas graves, ha sido ampliamente documentada en los últimos años y su desarrollo en el marco de la infección por el HIV permite una evolu-ción desafortunada de esta asociación morbosa presentando una ten-dencia importante hacia el desarrollo de patologías neoplásicas tales como la enfermedad de Kaposi y distintos tipos de linfomas.Se presentan dos casos de enfermedad de Castleman asociados a in-fección por HIV y HHV8 y se describe el contexto patogénico donde se desarrollan

Castleman ́s disease is a lymphoproliferative disorder of uncertain origin but, principally, related to dysfunction of follicular dendritic cells and impaired production of various cytokines, most of which have proinflammatory activity and are responsible for the symptoms that patients present.The relationship between Castleman ́s disease and HHV8, especially in severe forms, has been well documented in the last years. This morbid association is related to an unfortunate evolution in the context of HIV infection, presenting an increased risk of neoplastic disorders such as Kaposi ́s disease and various types of lymphomas.Two cases of Castleman ́s disease associated with HHV8 and HIV infection, and the pathogenic context in which they developed, are presented and described