Beyond the Basics of Castleman Disease

Many patients and doctors have questions about Castleman disease. We are here to help share what is known and to push forward research to answer those questions that are not yet answered.

Our main pages about Castleman disease can be found here. Additional information that is aimed at helping patients and loved ones learn more about the details of the disease and understand the scientific literature for Castleman disease are below.

An overview of Castleman disease
Criteria for diagnosis and categorization of Castleman disease
What causes Castleman disease?
How are different subtypes treated and what progress is being done?
Prognosis and survival
Specific criteria for diagnosis of iMCD-TAFRO

Castleman disease: A quick overview

  • Castleman disease (CD) describes a group of three disorders with similar lymph node appearance under the microscope.
  • A healthy immune system involves a complex and interconnected network of cells and inflammatory messengers (chemokines and cytokines), which signal for the immune system to activate. Lymph nodes are the home base for these immune cells.
  • In CD patients, inflammatory cells become hyper-activated and produce excess inflammatory messengers (chemokines and cytokines), particularly Interleukin-6 (IL-6), that lead to flu-like symptoms(e.g., fatigue, night sweats, nausea, weight loss), lymph node enlargement, and dysfunction of vital organs including the liver, kidneys, and bone marrow(e.g., fluid gain, confusion, bruising, bleeding.
  • CD is a rare disease but it does not discriminate – it can occur in people of all ages and genders. In the US there are an estimated 6,500 to 7,700 new CD cases diagnosed per year. [See article]
  • If we compare this number to the estimated number of new cases of lung cancer diagnosed in 2016, approximately 224,390, or to the number of US patients diagnosed with diabetes in 2014, 22 million, it’s easier to understand why most physicians may not have much, or any, experience in treating this disease.

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Diagnosis and categorization of Castleman disease

  • It is absolutely important to emphasize that diagnosis with Castleman disease requires a lymph node biopsy with CD features identified by a pathologist under the microscope. This is important so that patients without CD are not incorrectly diagnosed.
  • Lymph node features found in Castleman disease can also be seen in other diseases including cancers and autoimmune diseases (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, Systemic Lupus Erythematous, Rheumatoid Arthritis). This certainly makes diagnosis more challenging.
  • The above means that although a lymph node biopsy with CD features is required for CD diagnosis, it does not mean that the patient is automatically diagnosed  with CD. This is why your physician must rule out other diseases before a CD diagnosis is made.

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Types of Castleman disease

Main types: UCD and MCD
  • It is very important to understand the exact subtype of CD that you have because each subtype can require different treatment approaches.
  • Castleman disease is first classified based on the number of lymph node(s) or regions that are affected.
  • A patient with a single enlarged lymph node (or single region of enlarged lymph nodes) with CD features identified by a pathologist under the microscope is diagnosed with Unicentric Castleman disease (UCD).[Castleman’s original article].
  • A patient with enlarged lymph nodes in multiple regions of the body with the same CD features identified by a pathologist under the microscope, along with an array of specific symptoms and laboratory test results, is diagnosed with Multicentric Castleman disease (MCD). [Article on Diagnosis Guidelines].
MCD subtypes
  • Further, there are two subtypes of multicentric Castleman disease (MCD). If an MCD patient’s lymph node or blood sample is found to be infected with Human Herpes Virus-8 (HHV-8), she/he is considered to have HHV-8-associated MCD.
    • While many of these patients are HIV-positive, there are also HIV-negative individuals with HHV-8-associated MCD.
  • If a patient has multiple regions of enlarged lymph nodes with CD features identified by a pathologist under the microscope AND is HIV-negative and his/her lymph node and blood sample are HHV-8-negative, he/she may have HHV-8-negative or idiopathic MCD (iMCD).
Types of Idiopathic MCD
  • Some patients with iMCD experience a specific set of clinical symptoms that are described as the TAFRO subtype of iMCD. TAFRO stands for Thrombocytopenia (low platelet count), Anasarca (ascites, swelling), Fever (body temperature), Reticulin fibrosis (evaluated in bone marrow biopsy), and Organomegaly (lymphadenopathy and/or hepatomegaly/splenomegaly).
  • Symptom severity differs greatly among CD patients and can range from relatively asymptomatic to life-threatening multi-organ failure (e.g. kidney, liver, bone marrow, heart, lung failure).

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What causes Castleman disease?

  • All cases of UCD and about ½ of MCD are idiopathic—the cause is not known.
  • There are no known risk factors for UCD or idiopathic MCD, though the possibility of a genetic predisposition is under investigation.
  • For approximately ½ of MCD patients, HHV-8 infection causes and drives their disease. In these cases, HIV infection or another immune deficiency (i.e. genetic, immunosuppressants) enables HHV-8 to escape control by the immune system, replicate in lymph nodes, and signal the release of an excess of inflammatory chemicals (or cytokines), such as Interleukin-6 (IL-6).
  • More research is needed to understand why only a small proportion of HHV-8 + immunosuppressed patients develop Castleman disease, while the majority does not.
  • Although there are no reports of Castleman disease being contagious, it is important to state that patients and loved ones should exercise safe sex options to avoid HIV and HHV-8 infection, as these two viruses can lead to many other complications beyond Castleman disease.

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Treatment of Castleman disease subtypes

Following diagnosis, there are different types of specialist doctors who can treat Castleman disease including primary care physicians (PCP), surgeons, hematologist-oncologists, rheumatologists, immunologists, and infectious disease doctors, among others.

Unicentric Castleman disease (UCD)

  • Surgery is considered by experts to be the first-line treatment for almost all cases of UCD.
  • A patient is considered cured of UCD if their enlarged lymph node or nodes are removed completely and any previous laboratory abnormalities return to normal. Occasionally, UCD patients will continue to experience fatigue and other flu-like symptoms after a complete resection.
  • Sometimes, removing the enlarged lymph node(s) in their entirety is not possible. In these cases, treatments that are usually used to treat multicentric Castleman disease are sometimes needed.
  • There are no reported cases of UCD transforming into MCD

HHV-8-associated Multicentric Castleman disease (HHV-8-associated MCD)

  • Rituximab is highly effective in treating HHV-8-associated MCD.
  • Occasionally, etoposide, liposomal doxorubicin, and/or antivirals are also used. More extensive information about treatments for HHV-8-associated MCD can be found here.

HHV-8-negative/idiopathic Multicentric Castleman disease (iMCD)

  • The first-ever treatment guidelines for iMCD were published in the journal Blood in 2018. [See article here].
  • Anti-IL-6 medications (siltuximab, tocilizumab) with or without steroids are considered first-line treatment options.
  • Sometimes, rituximab or chemotherapy regimens used for blood cancers are used if a patient does not improve with anti-IL-6 therapy. More information on the current treatment guidelines can be found here.
  • Additional information about specific treatments that have been used for iMCD in the past and individual patient responses can be found here. [See article here]

POEMS-associated Multicentric Castleman disease (POEMS-associated MCD)

  • For patients with POEMS-associated multicentric Castleman disease, the target for treatment is the POEMS syndrome–and not the Castleman disease specifically.
  • First-line treatment for patients with a single plasmacytoma (a tumor made up of plasma cells) is radiation therapy.
  • Radiation for patients with a single plasmacytoma is often curative. If monoclonal plasma cells have spread throughout the body, chemotherapy with or without a stem cell transplant are treatment options. At times, steroids are also used. More information about POEMS diagnosis and treatment can be found in this article.

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Prognosis and Survival

  • The average length of survival after UCD diagnosis is greater than 10 years, and life expectancy is usually not changed by UCD.
  • MCD: The 5-year overall survival rate was 65% in a 2012 series of MCD cases (40% at 10 years; up from 13% in a 1993 series of 38 patients). Further progress in long-term outcome is anticipated with the advent of antibodies targeting the IL-6 signaling cascade, such as tocilizumab and siltuximab. The CDCN is currently spearheading a global patient research study to collect data on effective treatments and their relation to long term survival.

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Specific criteria for the diagnosis of iMCD TAFRO

The first-ever Diagnostic Criteria for HHV-8-negative/idiopathic multicentric Castleman disease has been developed by the CDCN and published in Blood. After reviewing 244 cases, meeting twice, and refining diagnostic criteria over a 15 month period, a panel of international experts came up with the below diagnostic criteria for idiopathic multicentric Castleman disease. 

Major Diagnostic Criteria (need both present to diagnose)

  • Histopathological lymph node features consistent with the idiopathic multicentric Castleman disease spectrum. Features along the idiopathic multicentric Castleman disease spectrum include (need Grade 2-3 for either regressive germinal centers or plasmacytosis at minimum): 
Regressive/atrophic/atretic germinal centers, often with expanded mantle zones composed of concentric rings of lymphocytes in an ‘onion skinning’ appearance Follicular dendritic cell prominence
Vascularity, often with prominent endothelium in the interfollicluar space and vessels penetrating into the germinal centers with a ‘lollipop appearance’ Sheet-like, polytypic plasmacytosis in the interfollicular space 
Hyperplastic germinal centers.
  • Enlarged lymph nodes (>1 cm in short-axis diameter) in two or more lymph node stations 


Minor Criteria (need at least 2 out of 11 criteria with at least 1 laboratory criterion) 

Laboratory:

  • Elevated CRP (greater than 10mg/L) or ESR (greater than 15mm/hr)

  • Anemia (hemoglobin less than 12.5g/dL for males, hemoglobin less than 11.5g/dL for 
females) 

  • Thrombocytopenia (platelet count less than 150k/μL) or thrombocytosis (platelet count 
greater than 400k/μL) 

  • Hypoalbuminemia (albumin less than 3.5g/dL) 

  • Renal dysfunction (eGFR <60 mL/min/1.73m2) or proteinuria (total protein >150mg/100ml) 

  • Polyclonal hypergammaglobulinemia (total gamma globulin or immunoglobulin 
G >1700mg/dL) 


 

Clinical:

  • Constitutional symptoms: night sweats, fever (>38oC), weight loss, or fatigue (>2 CTCAE lymphoma score for B-symptoms) 

  • Large spleen and/or liver 

  • Fluid accumulation: edema, anasarca, ascites, or pleural effusion 

  • Eruptive cherry hemangiomatosis or violaceous papules 

  • Lymphocytic interstitial pneumonitis 


 

Exclusion Criteria

In addition to the above criteria, the diagnosis requires that the following be excluded to rule out other conditions that mimic idiopathic multicentric Castleman disease.

Infection Related Disorders:

  • HHV-8 (infection can be documented by blood PCR, diagnosis of HHV-8-associated MCD requires positive LANA-1 staining by IHC, which excludes idiopathic multicentric Castleman disease) 

  • Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV (Detectable EBV viral load not necessarily exclusionary) 

  • Inflammation and adenopathy due to other uncontrolled infections, e.g. acute or uncontrolled CMV, toxoplasmosis, HIV, active tuberculosis 
 

Autoimmune/autoinflammatory diseases (requires full clinical criteria, detection of autoimmune antibodies alone is not exclusionary):

  • Systemic lupus erythematosus 

  • Rheumatoid arthritis 

  • Adult-onset Still disease 

  • Juvenile idiopathic arthritis 

  • Autoimmune lymphoproliferative syndrome (ALPS) 
 

Malignant/lymphoproliferative disorders (these disorders must be diagnosed before or at the same time as iMCD to be exclusionary):

  • Lymphoma (Hodgkin and non-Hodgkin) 

  • Multiple myeloma 

  • Primary lymph node plasmacytoma 

  • Follicular dendritic cell sarcoma 

  • POEMS syndrome


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References:
[Munshi2015] Munshi, Nikhil, et al. “Use of a claims database to characterize and estimate the incidence rate for Castleman disease.” Leukemia & lymphoma 56.5 (2015): 1252-1260.
[Fajbenbaum2017] Fajgenbaum, David C., et al. “International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease.” Blood 129.12 (2017): 1646-1657.
[Castleman1956] Castleman, Benjamin, Lalla Iverson, and V. Pardo Menendez. “Localized mediastinal lymph‐node hyperplasia resembling thymoma.” Cancer 9.4 (1956): 822-830.
[Waterston2004] Waterston, Ashita, and Mark Bower. “Fifty years of multicentric Castleman’s disease.” Acta Oncologica 43.8 (2004): 698-704.

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