Castleman Disease

Overview

• A lymphoproliferative disorder, also known as giant lymph node hyperplasia, lymphoid hamartoma, or angiofollicular lymph node hyperplasia.
• Classified by extent (unicentric vs multicentric) and, for multicentric disease, by driver: HHV-8-associated, POEMS-associated, or idiopathic (iMCD); iMCD requires excluding POEMS and HHV-8.
• IL-6 is the central driver cytokine. Excess IL-6 (and, in HHV-8-associated disease, a viral IL-6 homolog, vIL-6) produces the systemic inflammatory syndrome: cytokine excess, polyclonal B- and T-cell proliferation, and multi-organ dysfunction. This underlies the use of anti-IL-6-axis therapy (siltuximab, an anti-IL-6 monoclonal antibody; tocilizumab, an anti-IL-6-receptor antibody).

Histologic Variants

• Hyaline-vascular variant: most common in unicentric disease; regressed/atrophic germinal centers with expanded mantle zones ("onion-skinning"), radially penetrating sclerotic vessels ("lollipop" follicles). Usually asymptomatic.
• Plasma-cell variant: sheets of interfollicular plasma cells; more often associated with multicentric disease, systemic symptoms, and IL-6-driven laboratory abnormalities.
• Mixed and plasmablastic variants also occur (plasmablastic is typical of HHV-8-associated MCD).

Clinical Features & Labs

• Symptoms: lymphadenopathy, constitutional B symptoms, hepatosplenomegaly, and vascular leak syndrome (ascites, pleural effusion, edema).
• Labs: anemia, low albumin, and elevated CRP and ESR.

Criteria for Active Multicentric Disease

• Active HHV-8-associated MCD attack (ANRS criteria from HIV-MCD studies; not the iMCD diagnostic criteria): fever, and
• ↑ CRP >20 mg/L in the absence of another etiology, and
• At least 3 of the following MCD-related symptoms: lymphadenopathy/splenomegaly, edema, effusion/ascites, cough, autoimmune hemolytic anemia (AIHA), nasal obstruction, xerostomia, rash, CNS symptoms, jaundice.

Subtypes & Treatment

Idiopathic Multicentric Castleman Disease (iMCD)

• HHV-8-negative and HIV-negative; driven by dysregulated IL-6 (and other cytokines).
• Siltuximab (anti-IL-6 monoclonal antibody) is the preferred first-line therapy and is continued until progression; tocilizumab (anti-IL-6-receptor) is an alternative. Severe iMCD: siltuximab plus high-dose corticosteroids, then combination chemotherapy if no response.
• A recognized severe subset is TAFRO syndrome (Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis/renal dysfunction, Organomegaly), which tends to be more acute and may require corticosteroids and IL-6-directed therapy, sometimes with additional immunosuppression.

High-Yield Pearls

• Unicentric disease is cured by surgical resection; hyaline-vascular histology predominates.
• IL-6 is the key cytokine; siltuximab (anti-IL-6) is first-line for iMCD (HHV-8-negative, HIV-negative).
• HHV-8-associated MCD is usually (not always) HIV-associated and treated with rituximab-based therapy (rituximab (anti-CD20) depletes CD20-positive B cells, including the HHV-8 plasmablast reservoir (CD20 on infected plasmablasts is variable; exact mechanism incompletely established)); add antiretrovirals.
• Active HHV-8-associated MCD attack (from HIV-MCD/ANRS studies): fever + CRP >20 + at least 3 MCD-related symptoms. Not universal: iMCD is diagnosed by characteristic node histology + multicentric lymphadenopathy + at least 2 minor criteria (at least 1 laboratory) and exclusion of mimics; fever is not mandatory.
• Plasma-cell variant correlates with systemic, IL-6-driven disease; think TAFRO in acute iMCD with thrombocytopenia and anasarca.