iMCD is diagnosed according to evidence-based consensus diagnostic criteria, which require a thorough evaluation including patient history, physical exam, laboratory testing, radiologic imaging, and microscopic analysis (histology) of biopsied tissue from an enlarged lymph node. Diagnosis of iMCD requires clinical abnormalities, exclusion of other diseases, and a lymph node biopsy showing features consistent with Castleman disease. A lymph node biopsy alone is not sufficient to make the diagnosis. Laboratory testing Laboratory testing may demonstrate elevated C-reactive protein, decreased hemoglobin levels (anemia), low albumin levels, elevated creatinine, increased immunoglobulin levels, and abnormal (elevated or decreased) platelet counts. Patients may also have elevations of molecules involved in inflammation (cytokines), such as Interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). Medical imaging Radiologic imaging will demonstrate enlarged lymph nodes in multiple regions, which are typically 18F-fluorodoxyglucose (FDG) avid on positron-emission tomography (PET). Associated diseases iMCD is commonly seen in patients with POEMS syndrome, but it is unclear if iMCD occurs as an independent disease process or a manifestation of POEMS syndrome in these patients. Patients with iMCD have increased risk for solid tumors and cancers of the blood. Occasionally, patients with iMCD present with lymphocytic interstitial pneumonitis. TAFRO Syndrome iMCD patients with thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly syndrome (TAFRO syndrome) are considered to have a distinct clinical subtype of iMCD. Patients often have rapid progression of symptoms and frequently develop severe organ dysfunction. Compared to iMCD patients without TAFRO syndrome, iMCD patients with TAFRO syndrome are more likely to present with severe abdominal pain, low platelet levels, progressive renal dysfunction, and normal to mildly elevated immunoglobulin levels. While iMCD with TAFRO syndrome was first described in Japanese patients in 2010, cases of iMCD with TAFRO syndrome have since been reported in non-Japanese patients in many other countries. Classification Castleman disease describes a group of at least 3 distinct disorders—Unicentric Castleman disease (UCD), human herpesvirus 8 associated<unk>  Castleman disease (HHV-8-associated MCD), and<unk>  (iMCD). Identifying the correct subtype of the disease is important, as the three disorders vary significantly in symptoms, clinical findings, disease mechanism, treatment approach, and prognosis. * In Unicentric Castleman disease enlarged lymph nodes with characteristic microscopic findings are present in only a single lymph node region. * In the<unk>  subtypes of Castleman disease, enlarged lymph nodes with characteristic findings are present in multiple lymph node regions. The<unk>  variants of Castleman disease are further classified by known causes of the disease. * HHV-8-associated MCD is caused by uncontrolled infection with human herpesvirus 8 (HHV-8). * In<unk>  (iMCD) the cause of the disease is unknown<unk> . Testing for HHV-8 must be negative to diagnose iMCD.<unk>  iMCD may be further differentiated by the presence of associated diseases, such as polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome (POEMS syndrome), or by distinct clinical features, such as thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly syndrome (TAFRO syndrome). Diagnostic criteria Diagnosis of iMCD requires: the presence of both major criteria, multiple regions of enlarged lymph nodes as demonstrated by medical imaging; the presence of at least two minor criteria, at least one of which must be an abnormal laboratory test; and exclusion of diseases that can mimic iMCD. Major criteria 1: multiple regions of enlarged lymph nodes Radiologic imaging must demonstrate enlarged lymph nodes in multiple regions. Major criteria 2: microscopic analysis of lymph node biopsy consistent with iMCD The microscopic appearance (histology) of biopsied tissue from an enlarged lymph node must demonstrate a constellation of features consistent with Castleman disease. There are three patterns of characteristic histologic features associated with iMCD: * Hypervascular - regressed germinal centers, follicular dendritic cell prominence, hypervascularity in interfollicular regions, and prominent mantle zones with an “onion-skin” appearance. * Plasmacytic – increased number of follicles with large hyperplastic germinal centers and sheet-like plasmacytosis (increased number of plasma cells). * Mixed – features of both hypervascular and plasmacytic. iMCD most commonly demonstrates plasmacytic features; however, hypervascular features or a mixture of both hypervascular and plasmacytic features may also be seen in iMCD lymph nodes. The clinical utility of subtyping iMCD by histologic features is uncertain, as histologic subtypes do not consistently predict disease severity or treatment response. Staining with latency-associated nuclear antigen (LANA-1), a marker of HHV-8 infection, must be negative to diagnose iMCD. Minor criteria Patients must experience at least two of the following 11 minor criteria with at least one being an abnormal laboratory test. Laboratory tests: * Elevated C-Reactive Protein or erythrocyte sedimentation rate * Low hemoglobin levels (anemia) * Abnormal (low or high) platelet counts * Low albumin levels * Elevated creatinine * Increased levels of immunoglobulins (hypergammaglobulinemia) Clinical features: * Flu-like symptoms * Enlargement of the liver and/or spleen * Fluid accumulation (edema, ascites, pleural effusions) * Skin findings such as cherry hemangiomas or violaceous papules * Lymphocytic interstitial pneumonitis Diseases to be excluded Diagnosis requires exclusion of diseases that can present with similar clinical findings and similar appearance on microscopic analysis of tissue from an enlarged lymph node. Diseases that must be excluded in the diagnosis of iMCD include infectious diseases, such as HHV-8-associated MCD, Epstein-Barr virus mononucleosis, and reactive lymphadenopathy; autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis; and cancers, including lymphoma, multiple myeloma, and primary lymph node plasmacytoma.
Idiopathic multicentric Castleman disease
Unicentric Castleman disease
Chronic multifocal Langerhans cell histiocytosis
Follicular lymphoma
Fibrin-associated diffuse large B-cell lymphoma
HHV-8-associated MCD
AIDS-related lymphoma
Progressive nodular histiocytoma