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Idiopathic multicentric Castleman disease

Idiopathic multicentric Castleman disease is a subtype of Castleman disease, a group of lymphoproliferative disorders characterized by lymph node enlargement, characteristic features on microscopic analysis of enlarged lymph node tissue, and a range of symptoms and clinical findings.
People with iMCD have enlarged lymph nodes in multiple regions and often have flu-like symptoms, abnormal findings on blood tests, and dysfunction of vital organs, such as the liver, kidneys, and bone marrow.
iMCD has features often found in autoimmune diseases and cancers, but the underlying disease mechanism is unknown. Treatment for iMCD may involve the use of a variety of medications, including immunosuppressants and chemotherapy.
Castleman disease was named after Dr. Benjamin Castleman, who first described the disease in 1956. The Castleman Disease Collaborative Network is the largest organization focused on the disease and is involved in research, awareness, and patient support.

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1. Signs and symptoms
Patients with iMCD may experience enlarged lymph nodes in multiple lymph node regions; systemic symptoms ; enlargement of the liver and/or spleen; extravascular fluid accumulation in the extremities edema, abdomen ascites, or lining of the lungs pleural effusion; lung symptoms such as cough and shortness of breath; and skin findings such as cherry hemangiomas.

2. Causes
The cause of iMCD is not known and no risk factors have been identified. Genetic variants have been observed in cases of Castleman disease; however, no genetic variant has been validated as disease causing.
Unlike HHV-8-associated MCD, iMCD is not caused by uncontrolled HHV-8 infection.

3. Mechanism
The disease mechanism of iMCD has not been fully described. It is known that interleukin-6 IL-6, a molecule that stimulates immune cells, plays a role in some cases of iMCD. IL-6 levels measured in some patients with iMCD increase and decrease with corresponding changes in disease activity, mice treated with IL-6 develop features of iMCD, and blockade of the IL-6 pathway using the medications siltuximab and tocilizumab effectively treats some patients with iMCD. However, many patients with iMCD do not demonstrate elevated levels of IL-6 and IL-6 levels are not strongly correlated with response to treatment with anti-IL-6 medications. In cases where IL-6 does play a role, the underlying cause of elevated IL-6 levels and the cells responsible for producing IL-6 remain unknown.
Several theoretical mechanisms for iMCD have been proposed based on existing research and observed similarities between iMCD and other diseases that present with similar clinical findings and lymph node histology:
Pathogen – Human herpesvirus 8 HHV-8 is the known causative agent in HHV-8-associated MCD, which has very similar symptoms and findings to iMCD. While iMCD by definition is not caused by HHV-8, an unknown virus may cause the disease.
Autoinflammatory – A mutation in a gene controlling inflammatory systems may contribute to harmful activation of inflammatory pathways in patients with iMCD.
Autoimmune – The immune system may produce antibodies that target healthy cells in the body instead of bacteria and viruses. Self-directed antibodies are commonly seen in autoimmune diseases such as systemic lupus erythematous and rheumatoid arthritis.
Neoplastic – Genetic mutations that develop in mature cells somatic mutations may cause an overgrowth of abnormal cells as in cancers such as lymphoma.
There have been no reported cases of UCD transforming into iMCD.

4. Diagnosis
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.

4.1. 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.

4.2. Diagnosis Medical imaging
Radiologic imaging will demonstrate enlarged lymph nodes in multiple regions, which are typically 18F-fluorodoxyglucose FDG avid on positron-emission tomography PET.

4.3. Diagnosis 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, iMCD patients present with lymphocytic interstitial pneumonitis.

4.4. Diagnosis Classification
Castleman disease describes a group of at least 3 distinct disorders - Unicentric Castleman disease UCD, human herpesvirus 8 associated multicentric Castleman disease HHV-8-associated MCD, and idiopathic multicentric Castleman disease 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 idiopathic multicentric Castleman disease iMCD the cause of the disease is unknown idiopathic. Testing for HHV-8 must be negative to diagnose iMCD.
In Unicentric Castleman disease enlarged lymph nodes with characteristic microscopic findings are present in only a single lymph node region.
HHV-8-associated MCD is caused by uncontrolled infection with human herpesvirus 8 HHV-8.
In the multicentric subtypes of Castleman disease, enlarged lymph nodes with characteristic findings are present in multiple lymph node regions. The multicentric variants of Castleman disease are further classified by known causes of the disease.

4.5. Diagnosis Idiopathic multicentric Castleman disease
iMCD may be further differentiated by the presence of associated diseases, such as p olyneuropathy, o rganomegaly, e ndocrinopathy, m onoclonal protein, s kin changes syndrome POEMS syndrome, or by distinct clinical features, such as t hrombocytopenia, a nasarca, myelo f ibrosis, r enal dysfunction, and o rganomegaly syndrome TAFRO syndrome.

4.6. Diagnosis 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.

4.7. Diagnosis Major criteria 1: multiple regions of enlarged lymph nodes
Radiologic imaging must demonstrate enlarged lymph nodes in multiple regions.

4.8. Diagnosis 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.

4.9. Diagnosis 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:
Increased levels of immunoglobulins hypergammaglobulinemia
Abnormal low or high platelet counts
Elevated C-Reactive Protein or erythrocyte sedimentation rate
Low hemoglobin levels anemia
Low albumin levels
Elevated creatinine
Clinical features:
Lymphocytic interstitial pneumonitis
Fluid accumulation
Skin findings such as cherry hemangiomas or violaceous papules
Flu-like symptoms
Enlargement of the liver and/or spleen

4.10. Diagnosis 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.

5. Treatment
Due to the rarity of iMCD, data regarding treatment is limited and based on a combination of observational case series, case reports, and a single randomized clinical trial. Unlike UCD, for which surgery is the treatment of choice and curative for most patients, surgery is not effective in iMCD. Instead of surgical treatment, a variety of medications are used based on disease severity and a patients response to prior treatments. Siltuximab, a monoclonal antibody targeting IL-6, is the only medication approved by the United States Food and Drug Administration FDA for the treatment of iMCD; however, successful use of other medications has been reported in the literature.
In 2018, the first evidence-based consensus treatment guidelines for iMCD were published by an international group of experts in the field. In addition to creating a treatment algorithm for iMCD, these treatment guidelines established common definitions for disease severity and response to treatment.

5.1. Treatment Evaluation of iMCD Severity
Patients with iMCD are classified as having severe or non-severe disease based on the 5 criteria listed below. Patient with 2 or more of the below criteria are classified as having severe disease while patients with 0-1 of the criteria are classified as having non-severe disease.
Anasarca and/or ascites and/or pleural effusion and/or pericardial effusion
Estimated glomerular filtration rate eGFR 30 or Creatinine 3.0 mg/dL
Eastern Cooperative Oncology Group ECOG performance status ≥ 2
Hemoglobin ≤ 8.0 g/dL
Pulmonary involvement e.g. interstitial pneumonitis with dyspnea

5.2. Treatment Treatment response
Patients with iMCD are evaluated for treatment response based on changes in symptoms, sizes of involved lymph nodes, and laboratory testing. Each category is graded as a complete response, partial response, stable disease, or progressive disease. Overall treatment response is determined by the lowest category grade. For example, a patient with a complete laboratory response, a partial symptom response, and complete lymph node response would be given an overall treatment response of partial response. See below for descriptions of the criteria and grading of responses.

5.3. Treatment Laboratory Testing
Laboratory tests include all of the following: C-reactive protein, Hemoglobin, Albumin, and eGFR.
Partial response - 50% in all lab values
Complete response - All lab values within normal ranges
Stable disease - All lab values between