Castleman disease

Lore & Background

Castleman disease includes at least three distinct subtypes: unicentric Castleman disease (UCD), human herpesvirus 8 associated multicentric Castleman disease (HHV-8-associated MCD), and idiopathic multicentric Castleman disease (iMCD). These are differentiated by the number and location of affected lymph nodes and the presence of human herpesvirus 8, a known causative agent in a portion of cases. All forms involve overproduction of cytokines and other inflammatory proteins by the body's immune system as well as characteristic abnormal lymph node features that can be observed under the microscope. In the United States, approximately 4,300 to 5,200 new cases are diagnosed each year.

Reader's Guide

Castleman disease is significant as a rare and poorly understood group of disorders that challenge conventional disease classification. The three main subtypes—UCD, HHV-8-associated MCD, and iMCD—vary significantly in symptoms, clinical findings, disease mechanism, treatment approach, and prognosis. Correctly classifying the subtype is important for treatment decisions. For UCD, surgery is first-line; for HHV-8-associated MCD, rituximab is highly effective; for iMCD, anti-IL-6 therapy with siltuximab is the only FDA-approved treatment, though about half of patients do not improve. The Castleman Disease Collaborative Network is the largest organization dedicated to accelerating research and treatment for Castleman disease as well as improving patient care. The disease's legacy includes ongoing uncertainty about its fundamental nature—whether autoimmune, cancerous, or infectious—which drives continued research.

Did You Know?

• Castleman disease is named after Benjamin Castleman, who first described the disease in 1954.
• Siltuximab is the only FDA-approved treatment for idiopathic multicentric Castleman disease.
• HHV-8-associated MCD is most commonly diagnosed in HIV infected or otherwise immunocompromised individuals.

The Three Faces of a Rare Disorder

Castleman disease is not a single condition but a family of rare lymphoproliferative disorders united by enlarged lymph nodes, a sweeping array of inflammatory symptoms, and abnormal laboratory findings. What remains genuinely unresolved is how to categorize it: whether it belongs to the realm of autoimmune disease, malignancy, or infection is still an open question in medicine. The field recognizes at least three principal subtypes—unicentric Castleman disease (UCD), human herpesvirus 8–associated multicentric Castleman disease (HHV-8 MCD), and idiopathic multicentric Castleman disease (iMCD)—each distinguished by how many lymph node regions are involved, where they sit in the body, and whether HHV-8 is present as a causative agent. Getting the subtype right matters enormously because symptoms, underlying mechanisms, therapeutic strategies, and long-term outlook all shift dramatically from one category to the next. Every form shares a common thread of excessive cytokine and inflammatory-protein production by the immune system alongside distinctive microscopic lymph node abnormalities. In the United States, roughly 4,300 to 5,200 people receive a new diagnosis each year.

A Treatment Path for Every Subtype

Because the subtypes diverge so sharply in mechanism and behavior, no single therapeutic protocol fits all. For unicentric disease, surgical removal of the affected lymph node or nodes stands as the recommended first-line approach for every patient. When excision is not feasible, clinicians tailor therapy to the symptom profile: rituximab is suggested when enlarged nodes compress nearby structures, while anti-interleukin-6 therapy targets the inflammatory syndrome, with radiation reserved as a further option if those measures fall short. In HHV-8–associated multicentric disease, rituximab—designed to eliminate B lymphocytes—serves as the primary treatment and proves highly effective, though antivirals or cytotoxic chemotherapy may occasionally be added. Idiopathic multicentric Castleman disease, the most prevalent MCD form, is treated first with siltuximab, the sole FDA-approved agent for this subtype, or tocilizumab when siltuximab is unavailable. Patients who respond to siltuximab often enjoy durable, long-term remission. Yet roughly half of iMCD patients do not improve with anti-IL-6 therapy, prompting a switch to rituximab or sirolimus. Critically ill individuals showing progression may require chemotherapy and corticosteroids. POEMS-associated MCD, by contrast, is managed by treating the underlying POEMS syndrome itself.

The Microscopic Signature and the Cytokine Storm

At its core, Castleman disease is defined by what a pathologist sees under the microscope: a constellation of characteristic histological features in the tissue of enlarged lymph nodes that distinguishes it from other lymphoproliferative conditions. Beyond the structural abnormalities, every subtype shares a functional hallmark—uncontrolled overproduction of cytokines and other inflammatory proteins by the immune system, a phenomenon often described as a cytokine storm. The origin of that dysregulation, however, differs by subtype. In unicentric disease the trigger appears to be a genetic alteration within the lymph node tissue itself, behaving much like a benign tumor, and in roughly half of those cases the person shows no symptoms at all. HHV-8–associated multicentric disease stems from an uncontrolled viral infection, most often surfacing in individuals who are HIV-positive or otherwise immunocompromised and therefore unable to keep the virus in check. POEMS-associated MCD is driven by a cancerous cell population that floods the system with cytokines. Idiopathic multicentric Castleman disease remains the most mysterious: no virus, no identifiable cancer, no known infectious agent—just a persistent, unexplained inflammatory cascade.

From a 1954 Description to a Global Advocacy Network

The condition carries the name of Benjamin Castleman, the physician who first described the disease in 1954, and that single observation launched more than seven decades of ongoing investigation into what is now recognized as a family of distinct disorders. Despite that long history, fundamental questions persist. Doctors still debate whether Castleman disease is best classified as an autoimmune condition, a form of cancer, or an infectious disease, and the answer may differ depending on which subtype is under examination. The rarity of the condition—approximately 4,300 to 5,200 new diagnoses per year in the United States—has historically made large-scale research difficult, and many patients have struggled to find clinicians familiar with the disease. In response, the Castleman Disease Collaborative Network was established as the largest organization devoted exclusively to accelerating research, developing new treatments, and improving the quality of patient care. Its work spans all three major subtypes and the finer clinical subgroups within idiopathic multicentric disease, including iMCD-TAFRO and iMCD-IPL, ensuring that even the rarest presentations receive attention.