User:CDK55/idiopathic multicentric castleman disease

= Idopathic multicentric Castleman disease = Idiopathic multicentric Castleman disease is a subtype of Castleman disease (also known as giant lymph node hyperplasia, lymphoid hamartoma, or angiofollicular lymph node hyperplasia), a group of rare lymphoproliferative disorders that share characteristic features on microscopic analysis of affected lymph node tissue.

Castleman disease includes at least 3 distinct disorders—unicentric Castleman disease (UCD), human herpesvirus 8 associated multicentric Castelman disease (HHV-8-associated MCD), and idiopathic multicentric Castleman disease (iMCD)—which are differentiated by the number and location of affected lymph nodes and the presence of human herpesvirus 8, a known causative agent. Correctly classifying 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), multiple regions of lymph nodes are affected and no known cause for the disease is identified. It is less common than unicentric Castleman disease (UCD) and compared to UCD, symptoms are typically more severe, laboratory abnormalities must be present for diagnosis, and medication is used for treatment rather than surgery.

Castleman disease is named after Dr. Benjamin Castleman. The Castleman Disease Collaborative Network (CDCN) is the largest organization related to the disease, focusing on advancing research efforts, raising awareness, and providing patient support.

Classification
Castleman disease is classified into unicentric and multicentric variants based on the number and location of affected lymph nodes. The two multicentric subtypes of Castleman disease, human herpesvirus 8 associated multicentric Castleman disease (HHV-8-associated MCD) and idiopathic multicentric Castleman disease (iMCD), are differentiated from UCD by the involvement of multiple regions of lymph nodes and differentiated from one another by the presence of infection with human herpesvirus 8.

iMCD may be further differentiated into subtypes 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).

Symptoms
Patients with iMCD commonly report enlarged lymph nodes, rashes, swelling of the extremities or abdomen, and systemic symptoms, such as fever, night sweats, unintended weight loss, and fatigue.

Findings
In patients with iMCD, physical exam may reveal enlarged lymph nodes in multiple regions, skin findings such as cherry hemangiomas, signs of extravascular fluid accumulation (edema, ascites, pleural effusions), or enlargement of the liver and/or spleen. Laboratory testing may show low hemoglobin levels (anemia), abnormal platelet counts, low albumin levels, elevated inflammatory markers, kidney dysfunction, increased levels of immunoglobulins, and elevation of specific small molecules involved in cellular signaling (cytokines), such as interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). Radiologic imaging will demonstrate enlarged lymph nodes in multiple regions, which are typically 18F-fluorodoxyglucose (FDG) avid on positron-emission tomography (PET).

Pathology
The microscopic appearance (histology) of biopsied tissue from lymph nodes affected by iMCD will be consistent with Castleman disease. There are two 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 sheetlike plasmacytosis (increased number plasma cells).

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 for HHV-8 infection, will be negative.

TAFRO Syndrome
Thrombocytopenia, anasarca, myelfibrosis, renal dysfunction, and organomegaly syndrome (TAFRO) is a distinct clinical presentation of iMCD. It is the most severe presentation of Castleman disease, with rapid progression of symptoms and development of 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. Patients with TAFRO syndrome often require intensive care unit level treatment, including breathing support with mechanical ventilation and treatment with dialysis for kidney failure.

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.

Causes
iMCD does not have any known risk factors. Genetic variants have been identified in cases of Castleman disease ; however, no genetic variant has been validated as disease causing.

HHV-8-associated MCD is known to be caused by infection with human herpesvirus-8.

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 off of existing research and observed similarities between iMCD and other diseases that present with similar clinical findings and lymph node histology :


 * 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.
 * Autoinflammatory – A mutation in a gene controlling inflammatory systems may contribute to harmful activation of inflammatory pathways in patients with iMCD.
 * Neoplastic – Genetic mutations that develop in mature cells (somatic mutations) may cause an overgrowth of abnormal cells as in cancers such as lymphoma.
 * 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.

There have been no reported cases of UCD transforming into iMCD.

Epidemiology
There are approximately 1500-1800 new cases of iMCD diagnosed per year in the United States. iMCD can occur at any age, but the median age at presentation is approximately 50 years old. There is a slightly increased incidence of iMCD in women.

There have been no published epidemiologic studies of Castleman disease outside of the United States; however, there has been no published data demonstrating increased or decreased incidence of Castleman disease in specific regions or ethnicities.

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. Medication selection is based off of disease severity and response to prior treatments.

Based on evidence from a randomized control trial, siltuximab is the only medication approved by the United States Food and Drug Administration (FDA) for the treatment of iMCD. Siltuximab is typically used in all patients with iMCD—regardless of measured IL-6 levels—unless a patient has failed to respond to the medication in the past or has a contraindication to the medication. It results in at least partial response in approximately one third of patients. If siltuximab is unavailable, treatment targeting the IL-6 pathway with tocilizumab is commonly used. Corticosteroids may be added to siltuximab in more severe cases of disease. For patients with life threatening disease who do not rapidly respond to siltuximab and corticosteroids, aggressive treatment with chemotherapy and/or immunosuppressant medications is typically initiated. Following improvement in disease status, maintenance therapy with siltuximab, or an immunosupressant medication, is typically continued indefinitely, as withdrawal of such medications can lead to relapse.

Follow-up
Patients with iMCD require routine assessment of treatment response and disease progression. Follow-up visits should include evaluation of symptoms, physical examination, laboratory testing, and radiologic imaging.

Prognosis
iMCD is a chronic disease which may vary in disease severity for patients over time. Some patients have longstanding stable disease while others suffer flares of severe disease that may improve with treatment. Successful treatment controls symptoms and organ dysfunction associated with iMCD, rapidly improves symptoms and organ dysfunction during disease flares, and prevents future disease flares.

Observed survival in a recent study of iMCD patients was 92% at 2 years, 76% at 5 years, and 59% at 10 years.

History
Castleman disease was first described by Dr. Benjamin Castleman in 1954.

Castleman Disease Collaborative Network
The Castleman Disease Collaborative Network (CDCN) is the largest organization related to Castleman disease. It is a global collaborative network focused on Castleman disease research and patient support.