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= Human herpesvirus 8 associated multicentric Castleman disease = Human herpesvirus 8 associated 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. The three disorders vary significantly in symptoms, clinical findings, disease mechanism, treatment approach, and prognosis.

In human herpesvirus 8 associated multicentric Castelman disease (HHV-8-associated MCD), multiple regions of lymph nodes are affected and infection with human herpesvirus 8 (HHV8, also known as Kaposi sarcoma-associated herpesvirus) is present. It is less common than unicentric Castleman disease (UCD) and idiopathic multicentric Castleman disease (iMCD), and is most frequently diagnosed in patients with human immunodeficiency virus (HIV). Compared to UCD and iMCD, HHV-8-associated MCD presents with similar symptoms and clinical findings to iMCD. While UCD is readily treatable with surgery, HHV-8-associated MCD, like iMCD, is treated with medications, as surgery is ineffective.

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 unicentric Castleman disease by the involvement of multiple regions of lymph nodes and differentiated from one another by the presence of infection with human herpesvirus 8.

Symptoms
Patients with HHV-8-associated MCD commonly report enlarged lymph nodes, rashes, swelling of the extremities, abdominal distention, shortness of breath, cough, and systemic symptoms, such as fever, night sweats, unintended weight loss, and fatigue.

Findings
In patients with HHV-8-associated MCD, physical exam may reveal enlarged lymph nodes in multiple regions, skin findings such as cherry hemangiomas or Kaposi sarcoma, 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). Radiologic imaging will demonstrate enlarged lymph nodes in multiple regions, which are typically 18F-fluorodoxyglucose (FDG) avid on positron-emission tomography (PET).

Pathology
Unlike UCD and iMCD, which can present with a spectrum of features on microscopic analysis (histology) of biopsied tissue from affected lymph nodes, only a plasmablastic pattern of histologic features has been described in HHV-8-associated MCD. Plasmablastic features are similar to the plasmacytic features seen in iMCD and UCD, with both demonstrating increased plasma cells in interfollicular spaces. Plasmablastic features are differentiated from plasmacytic features by increased numbers of plasmablasts in follicular mantle zones6.

Staining with latency-associated nuclear antigen (LANA-1), a marker for HHV-8 infection, will be positive.

Associated Diseases
HHV-8-associated MCD is most commonly seen in patients with human immunodeficiency virus (HIV), but can be seen in patients without HIV as well.

Patients with HHV-8-associated MCD are often found to have Kaposi sarcoma, a cancer caused by the HHV-8 virus and most commonly seen in patients with HIV. Patients with HHV-8-associated MCD have been observed to be at greater risk of developing lymphoma.

Causes
HHV-8-associated MCD is known to be caused by infection with human herpesvirus-8. The HHV-8 virus is commonly found in healthy individuals showing no signs of disease, but it is also known to cause diseases such as Kaposi sarcoma and HHV-8-associated MCD. Diseases caused by HHV-8 are seen most frequently in the setting of immune dysfunction related to factors such as HIV infection or use of immunosuppressant medications; however, HHV-8-associated diseases, including HHV-8-associated MCD, have been reported in otherwise healthy individuals.

Mechanism
The HHV-8 virus, which infects B cells and plasmablasts in lymph nodes, causes infected cells to release proinflammatory cytokines, signaling molecules that increase the activity of immune cells. Infection of immune cells and release of proinflammatory cytokines are responsible for the lymph node changes, systemic symptoms, and organ dysfunction seen in HHV-8-associated MCD.

In particular, HHV-8 infection leads to increased levels of Interleukin-6 (IL-6), a cytokine known to play a role in other forms of Castleman disease. The HHV-8 virus contains a gene coding for a viral variant of IL-6. Cells infected by HHV-8 produce both viral IL-6 and human IL-6, both of which contribute to the increased B cell proliferation and clinical findings seen in HHV-8-associated Castleman disease.

Epidemiology
No epidemiologic study has been published estimating the incidence for HHV-8-associated MCD in the general population; however, it is estimated that approximately 300 patients per year with HIV are diagnosed with HHV-8-associated MCD in the United States. While rates of Kaposi sarcoma in HIV patients—which like HHV-8-associated MCD is caused by uncontrolled HHV-8 infection—decreased as treatment with antiretroviral therapy became more common, rates of Castleman disease increased over the same time period. It is unclear whether this finding represents a true increase in prevalence of HHV-8-associated MCD despite improved control of HIV, or increased recognition and diagnosis of the disease during this time period.

There have been no published epidemiologic studies of Castleman disease outside of the United States; however, rates of HHV-8-associated MCD may vary in different populations based on the prevalence of infection with HHV-8.

Diagnosis
HHV-8-associated MCD is diagnosed based on patient history, physical exam, laboratory testing, radiologic imaging, and microscopic analysis (histology) of biopsied tissue from an affected lymph node.

Formal criteria for diagnosis of HHV-8-associated MCD have not been published; however, diagnosis requires involvement of lymph nodes in multiple regions, histologic changes consistent with Castleman disease on lymph node biopsy, and presence of HHV-8 infection by LANA-1 lymph node staining. HIV testing is useful for management, but a positive result is not necessary for diagnosis.

Treatment
Data regarding treatment for HHV-8-associated MCD is limited and draws from a combination of observational case series and case reports. There have been no randomized controlled trials investigating treatment options for HHV-8-associated MCD. Surgical removal of affected lymph nodes, the standard treatment for UCD, is ineffective in HHV-8-associated MCD. Like iMCD, HHV-8-associated MCD is treated with medications. Factors influencing medication selection include disease severity, presence of HIV, presence of Kaposi sarcoma, and response to prior treatments.

Rituximab, a drug that depletes B cells, is the first line agent for patients with HHV-8-associated MCD and is recommended in all patients with proven HHV-8-associated MCD unless they have a contraindication to the medication or have failed treatment with the medication in the past. For patients who present with severe organ dysfunction, develop worsening organ dysfunction despite treatment with Rituximab, or have concurrent Kaposi sarcoma, additional chemotherapeutic agents are added to Rituximab. All patients with HIV should continue or initiate treatment with antiretroviral therapy. Antiviral medications targeted at HHV-8, such as valganciclovir, may be used in patients with poorly controlled HIV or concurrent Kaposi sarcoma.

Rituximab may be discontinued once clinical and laboratory evidence of active disease resolve or continued as maintenance therapy. Patients who responded to Rituximab but have recurrent HHV-8-associated MCD after discontinuing the medication typically respond to retreatment with Rituximab.

Follow-up
Patients with HHV-8-associated MCD are typically seen at routine intervals for assessment of treatment response and disease progression. Follow-up visits may include evaluation of symptoms, physical examination, laboratory testing, and radiologic imaging.

Prognosis
Outcomes in HHV-8-associated MCD have improved significantly since treatment with rituximab has become more common. In one published case series from an experienced center, observed survival in a cohort of HIV patients with HHV-8-associated MCD was 94% at 2 years and 90% at 5 years.

History
Castleman disease was first described by Dr. Benjamin Castleman in 1954. In 1995, the association between HHV-8 and Castleman disease was described in patients with HIV.

Castleman Disease Collaborative Network (CDCN)
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.