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.

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.

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.

Enfermedad de Castleman en glándula salival: informe de un caso pediátrico / Castleman disease in salivary gland: report of a pediatric case

La enfermedad de Castleman (EC) es una rara entidad linfoproliferativa benigna caracterizada por el crecimiento no neoplásico progresivo de los ganglios linfáticos en cualquier parte del cuerpo, aunque en la mayoría de los casos (60%) afecta el mediastino y, con una muy baja frecuencia, compromete la región de la cabeza y el cuello, incluidas las glándulas salivales. Representa un desafío diagnóstico para el médico porque se presenta con síntomas y signos inespecíficos. Existen dos subtipos: uno localizado en forma de adenopatía sin síntomas generales y otro multicéntrico con compromiso de varios grupos ganglionares y con manifestaciones clínicas sistémicas y alteraciones del laboratorio. El diagnóstico requiere un examen físico completo y exámenes complementarios (laboratorio, ecografía, tomografía computarizada o resonancia magnética nuclear o ambas, punción aspiración con aguja fina) y se confirma a través del análisis histopatológico. El tratamiento es quirúrgico, pero la forma multicéntrica requiere además un tratamiento adyuvante. A pesar de su localización inusual en las glándulas salivales, la EC debería ser considerada entre los diagnósticos diferenciales, sobre todo ante la sospecha de procesos linfoproliferativos. Se describe en este trabajo el caso de una paciente pediátrica con diagnóstico de EC localizada en la glándula submaxilar, y se realizó una revisión de la literatura. (AU)

Castleman disease (CD) is a rare lymphoproliferative entity characterized for a non ­ neoplasic progressive growth of the lymph nodes in any part of the body; nevertheless it usually affects the mediastinum (60 %), and with less frequency, it compromises the head and neck region, including the salivary glands. It represents a diagnostic challenge for the doctor, because it has nonspecific symptoms and signs. There are two subtypes: the localized form, that generally is presented through an adenopaty without systemic symptoms, and a multicentric form that compromises several nodal groups and has systemic symptoms and laboratory abnormalities. Diagnosis requires a complete physical examination and complementary exams (blood tests, ultrasonography, computed tomography and/or magnetic resonance, fine needle puncture ­ aspiration), and the final diagnosis is through histopathological analysis. The treatment is surgery, but multicentric form requires adyuvant treatment. Although its unusual presentation in salivary glands, CD should be considered between differential diagnosis, especially when we are thinking of lymphoproliferative entities. In this article, we present a case of a pediatric patient with diagnosis of CD of submaxilar gland and we review the literatura about this disease with special attention in the salivary glands location. (AU)

Doença de Castleman e síndrome de Poems: relato de caso e revisão da literatura / Castleman disease and Poems syndrome: case report and review

A Doença de Castleman é uma desordem linfoproliferativa que apresenta relação etiológica com o herpes vírus tipo 8 e o HIV, manifestando-se de duas formas distintas. A forma unicêntrica é benigna, não cursa com sintomas sistêmicos e geralmente é curada com a ressecção cirúrgica. A forma multicêntrica geralmente apresenta-se com linfadenopatia generalizada, febre, emagrecimento, entre outras manifestações sistêmicas e pode estar associada a malignidades, entre as quais a síndrome de POEMS (polineuropatia, organomegalia, endocrinopatia, gamopatia monoclonal e alterações de pele). Relatamos o caso de um homem de 50 anos que se apresentava com emagrecimento, febre e linfadenopatia, associado a gamopatia monoclonal, organomegalia, endocrinopatia e neuropatia, cujo diagnóstico foi de Doença de Castleman cursando com síndrome de POEMS.

Castleman’s disease is a lymphoproliferative disorder related with human herpesvirus 8 and HIV, presenting in two different ways. The unicentric form is benign, doesn’t have systemic symptoms and is usually cured with surgery. The multicentric form usually presents with generalized lymphadenopathy, fever, weight loss, and other systemic manifestations and it can be associated with malignancy, especially POEMS syndrome. We report a case of a 50 year old man presenting with weight loss, fever and lymphadenopathy, associated with monoclonal gammopathy, organomegaly, endocrinopathy and neuropathy, which diagnosis was Castleman’s disease with POEMS syndrome.

Multicentric angiofollicular lymph node hyperplasia in ulcerative colitis. A case report.

Multicentric angiofollicular lymph node hyperplasia (MAFH) is a rare disorder which has been associated with various disease entities. This is the first report of its association with ulcerative colitis. Details of lymph node histology and views on pathogenesis are given.