Key Ideas

KSHV/HHV8-associated multicentric Castleman disease (MCD) shares clinical features with idiopathic multicentric Castleman disease but has a distinct viral cause, potentially concurrent KSHV-associated conditions (Kaposi sarcoma and/or KSHV-associated lymphomas), and is effectively treated with the anti-C20 monoclonal antibody, rituximab. Evaluation for other KSHV-associated diseases is important as it alters the treatment for MCD. 

A Distinct Viral Cause, With a Distinct Geographic Footprint

Unlike most human herpesviruses, which infect people broadly across the globe, Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus 8 or HHV-8) is concentrated in specific populations: certain areas of sub-Saharan Africa, Latin America, and, within the United States, people who have emigrated from those regions, along with men who have sex with men and people living with HIV. KSHV infection is a prerequisite for this form of MCD; without it, this specific diagnosis is not possible.

Clinically, KSHV-associated MCD looks similar to idiopathic multicentric Castleman disease, but a few features can tip off the diagnosis: the presence of other concurrent KSHV-associated diseases (roughly half of these patients will also have Kaposi sarcoma or one of the associated lymphomas), and a patient with well-controlled HIV who develops lymphadenopathy and waxing an dawning inflammatory signs and symptoms.

Three Related Diseases From the Same Virus

KSHV causes three additional distinct conditions, which can occur separately, together, or sequentially in the same patient with MCD over time, making it important to actively look for all three whenever one is diagnosed, since it changes MCD treatment:

  • Kaposi sarcoma, an endothelial cell tumor of the skin that can also involve lymph nodes and internal organs, most commonly the lungs and GI tract.

  • Primary effusion lymphoma, a rare lymphoma presenting with malignant fluid collections in body cavities, with a distinct natural history from other lymphomas.

  • KSHV-associated large B-cell lymphoma, which presents with nodal or extranodal involvement generally without  malignant effusions.

A Key Treatment Pitfall: Rituximab Can Worsen Concurrent Kaposi Sarcoma

If a patient has KSHV-associated MCD alone, without other concurrent KSHV-driven disease, treatment is the anti-CD20 monoclonal antibody, rituximab. It is essential to know whether a patient with MCD also has concurrent Kaposi sarcoma as rituximab can worsen or trigger a flare of Kaposi sarcoma. For patients with both conditions, it is important to Kaposi sarcoma-directed therapy, such as low-dose liposomal doxorubicin (dosed at 20 mg/m², well below dosing for other cancers), alongside rituximab. For patients with concurrent lymphoma, anthracycline-based combination chemotherapy is required. Although these are generally CD20-negative lymphomas, rituximab should be added at least for the first cycle since patients frequently have concurrent MCD or KSHV-associated inflammatory signs/symptoms, which rituximab can treat.

For patients with HIV, all patients should be receiving antiretroviral therapy and initiation of antiretroviral therapy should not be delayed to start MCD treatment. Certain KSHV-associated conditions can transiently worsen when antiretroviral therapy is first started, an important point to anticipate and manage rather than a reason to delay treatment.

KSHV-Associated MCD Tends to Remit; Idiopathic MCD Tends to Relapse

An important prognostic distinction: most patients with KSHV-associated MCD whose disease responds to treatment will have permanent remission, with only about 10% of patients experiencing a subsequent MCD flare. When patients have a subsequent MCD flare, rituximab can be used again to put the disease into remission. Idiopathic multicentric Castleman disease (the HHV-8-negative form) behaves quite differently, with patients often spending considerably more cumulative time in active disease flares over their lifetime.

A Related, Likely Overdiagnosed Syndrome

A related condition, KSHV-associated inflammatory cytokine syndrome (sometimes called KICS), was described roughly two decades ago in patients who had clinical features of KSHV-associated hyperinflammatory disease but did not meet the pathologic criteria for a formal MCD diagnosis (which currently requires a lymph node biopsy). KICS should remain a diagnosis of exclusion once all other KSHV-associated diseases have been ruled out. Data published within the past year suggest that many of these patients likely have undiagnosed KSHV-associated MCD. This is important as there is effective treatment for MCD. Newer research also suggests lambda-restricted polyclonal KSHV-infected plasmablasts, the driver of disease in KAHSV-associated MCD, may be detectable in peripheral blood and other body fluids, potentially allowing MCD to be diagnosed without requiring an invasive lymph node biopsy, though this approach is not yet standard practice.

For Patients

Castleman disease caused by a specific virus called KSHV (also known as HHV-8) is a distinct form of the condition from the more commonly discussed "idiopathic" form, and it is important to distinguish these two forms of Castleman disease because they have different treatments. This virus mainly affects specific populations globally, including people from certain parts of sub-Saharan Africa and Latin America, men who have sex with men, and people living with HIV.

This same virus can also cause a type of skin cancer called Kaposi sarcoma, as well as two rare types of lymphoma, and patients with one of these conditions should be evaluated for the other conditions, since having more than one condition often changes the treatment plan. Castleman disease caused by KSHV is treated with a common antibody drug called rituximab. This drug is very effective in Castleman disease but can worsen Kaposi sarcoma if a patient has both conditions at the same time. Specific treatment for Kaposi sarcoma can be added to rituximab to treat both conditions.

The good news is that KSHV-associated Castleman disease responds to treatment in most patients, and most patients do not need more treatment for Castleman disease in the future, unlike the idiopathic form of the disease, which can return more frequently.

Anyone diagnosed with Kaposi sarcoma, KSHV-associated Castleman disease, or living with HIV and experiencing unexplained lymph node swelling or systemic inflammatory symptoms should ask their care team about testing for all three related KSHV-associated conditions, since finding one raises the chance of having another.

Key Takeaways

  • KSHV/HHV8-associated multicentric Castleman disease requires infection with Kaposi sarcoma herpesvirus and is concentrated in specific global populations, distinguishing it from idiopathic (HHV-8-negative) multicentric Castleman disease.

  • The same virus causes three related conditions (Kaposi sarcoma, primary effusion lymphoma, and KSHV-associated large B-cell lymphoma), which can occur together or sequentially and patient should be evaluated for all of these conditions during work-up for MCD.

  • Rituximab is very effective against KSHV-associated MCD.  KSHV-associated MCD generally remains in long-term remission with rituximab (only about 10% of patients experience relapse), in contrast to idiopathic MCD, which tends to have a more relapsing course.

  • Rituximab can lead to the development or progression of Kaposi sarcoma; combining rituximab with Kaposi sarcoma-directed therapy (such as low-dose liposomal doxorubicin) is important for patients with both conditions.

  • Antiretroviral therapy should be started immediately in all patients with HIV and KSHV-associated Active MCD should not delay initiation of antiretroviral therapy. 

  • A related hyperinflammatory syndrome (KICS) may represent underdiagnosed KSHV-associated MCD in many cases, and newer blood-based diagnostic approaches for KSHV-associated MCD may eventually reduce reliance on lymph node biopsy.

References

  1. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017.

  2. Patel R, Lurain K, Yarchoan R, Ramaswami R. Clinical management of Kaposi sarcoma herpesvirus-associated diseases: an update on disease manifestations and treatment strategies. Expert Rev Anti Infect Ther. Jul–Dec 2023;21(9):929–941. doi:10.1080/14787210.2023.2247161

  3. Ramaswami R, Lurain K, Polizzotto MN, et al. Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases. Blood Adv. Mar 23 2021;5(6):1660–1670. doi:10.1182/bloodadvances.2020004058

  4. Lurain K, Yarchoan R, Uldrick TS. Treatment of Kaposi Sarcoma herpesvirus-Associated Multicentric Castleman Disease. Hematol Oncol Clin North Am. Feb 2018;32(1):75–88. doi:10.1016/j.hoc.2017.09.007

  5. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017.