Featured rare disease

On this page, we highlight one of the many rare diseases. We feature a new rare disease periodically; in this way we can raise awareness and understanding of rare diseases one disease at a time, raising people’s awareness not only that the disease exists but what it is and how to recognise it. If you have been diagnosed with one of the diseases highlighted and would like to share a story about your journey please contact us at enquiries@nzord.org.nz and we can arrange to put it up on our website.

Castleman’s disease

What is Castleman’s disease?

Castleman’s disease (CD) is a rare disorder characterised by non-cancerous growths, that may develop in the lymph node tissue around the body, also known as a lymphoproliferative disorder. CD is not cancer, however one form of this disease (known as multicentric Castleman’s disease (MCD)) acts very much like lymphoma. And like lymphoma, CD is often treated with chemotherapy or radiation therapy.

All types of CD may affect individuals of any age, and affects males and females in equal numbers. However, the plasma cell type has greater prevalence among young males and females. Children are rarely affected by this disorder, and persons with HIV are at increased risk of developing MCD.

Understanding Castleman’s disease

To understand this disease it helps to know about the body’s lymph system. Lymphoid/lymphatic tissue is the main part of the immune system. It is formed by different types of cells that work together to help the body fight infections. The main cells in lymphoid tissue are lymphocytes, a type of white blood cell. There are two main types of lymphocytes: B cells and T cells.

Lymphoid tissue is found in many places throughout the body, including:

  • Lymph nodes: bean-sized collections of lymphocytes found in small groups throughout the body, including inside the chest, abdomen, and pelvis. They can sometimes be felt under the skin in the neck, under the arms, and in the groin.
  • Thymus: a small organ behind the upper part of the breastbone and in front of the heart. The thymus plays a vital role in development of T cells.
  • Spleen: an organ under the lower part of the rib cage on the left side of the body. The spleen makes lymphocytes and other immune system cells to help fight infection. It also stores healthy blood cells and helps filter the blood.
  • Tonsils and adenoids: collections of lymphoid tissue at the back of the throat. They help protect the body against germs that are breathed in or swallowed.
  • Bone marrow: the soft inner part of certain bones that makes red blood cells, blood platelets, and white blood cells (including lymphocytes).
  • Digestive tract: the stomach, intestines, and other organs, which also have lymphoid tissue.

A healthy immune system involves a complex and interconnected network of cells and inflammatory messengers (cytokines), which signal for the immune system to activate. Lymph nodes are the home base for immune cells.

Types of CD

CD is a group of three heterogeneous (having widely dissimilar elements or constituents) inflammatory disorders that occur in people of all ages. CD is classified first based on the number of lymph node regions that are affected, single or multiple, namely unicentric CD (UCD) and multicentric CD (MCD). MCD is also divided into forms with or without human herpes virus-8 (HHV-8):

  • In UCD, a single region of enlarged lymph nodes occurs, such as a single, solid growth within lymphatic tissue in the chest, stomach, or neck. Growths may also occur in other lymphatic tissue throughout the body. Usually the growths represent abnormal enlargement of the lymph nodes normally found in these areas.
  • IN MCD, multiple regions of nodes are enlarged, with or without the presence of HHV-8.

In the unicentric hyaline-vascular variant of CD, individuals exhibit no symptoms (asymptomatic) or may develop a non-cancerous (benign) growth in the lymph tissue, most frequently in the chest. Evident symptoms for this type of CD are usually secondary to the size and location of the growth. For example, a growth may form next to a vein, resulting in a bulge and possible obstruction in the involved blood vessel.

In the plasma cell variants of CD, individuals may exhibit a variety of symptoms including fever, fatigue, excessive sweating, weight loss, skin rash, early destruction of red blood cells, leading to unusually low levels of circulating red blood cells (hemolytic anemia), and/or abnormally elevated amounts of certain immune factors in the blood (hypergammaglobulinemia). These symptoms are also occasionally seen with the multicentric hyaline vascular variant.

In CD patients, the inflammatory cells become activated and produce an excess of inflammatory messengers (cytokines), particularly interleukin-6 (IL-6), which can lead to dysfunction of the organ. This dysfunction includes lymph node enlargement, flu-like symptoms (e.g., fatigue, night sweats, nausea, weight loss), and dysfunction of vital organs, including the liver, kidneys, and bone marrow (e.g., fluid gain, confusion, bruising, bleeding).

Diagnosis

CD is a wide ranging disease that is difficult to diagnose, classification starting with the number of lymph node regions affected .

There is no official diagnostic criteria for CD and the lymph node features found in CD can also be seen in other diseases including cancers and autoimmune diseases (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, systemic lupus erythematous, rheumatoid arthritis).

 Unicentric CD (UCD)HHV-8-associated multicentric CD (HHV-8+MCD)Idiopathic multicentric CD (iMCD)
% of Cases 1/2 1/4 1/4
Regions Affected Enlarged lymph node in one region Multiple regions of enlarged nodes Multiple regions of enlarged nodes
Common Age of Diagnosis Mostly in children and young adults, but can occur at any age Mostly in adults 40–60 years old, but can occur at any age Mostly in adults 40–60 years old, but can occur at any age
Gender Slightly more common in females More common in males Slightly more common in males
Symptoms Usually shows no symptoms, but there can be discomfort associated with an enlarged lymph node and occasionally multicentric Castleman disease-like symptoms Wide range from mild flu-like symptoms to severe episodes of sepsis-like, life-threatening organ failure and death Wide range from mild flu-like symptoms to severe episodes of sepsis-like, life-threatening organ failure and death
Causes Unknown, but can be associated with paraneoplastic pemphigus – a deadly autoimmune disorder that occurs secondary to an underlying malignancy Human herpes virus-8 (HHV-8) is responsible for triggering the disease, and patients are often immunocompromised (e.g., HIV, organ transplantation) Unknown
Treatment Surgical removal of the enlarged node usually cures the patient Well controlled with B-cell depletion therapy with rituximab Treatment typically involves anti-IL-6 therapy, with or without chemotherapy
Chance of Relapse Rare Less common than iMCD with close monitoring Common, but varies depending on treatment used
Cure With surgical removal most symptoms go away. There have not been any reported cases of UCD transforming into MCD. None None
5-year Survival Rate 90%; 1 in 10 die 62% - 1 in 3 die; new data shows patients treated with rituximab have a 90% 5-year survival rate 62%; 1 in 3 die

Symptoms

Patients are commonly misdiagnosed with other illnesses or told they have cancer before being correctly diagnosed with CD.

CD Signs and Symptoms

The first-ever diagnostic criteria for HHV-8-negative/idiopathic MCD has been developed by the CDCN and published in Blood, and summarised below:

Major diagnostic criteria (need both present to diagnose)

  1. Histopathological lymph node features consistent with the idiopathic MCD 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
  2. Enlarged lymph nodes (>1cm 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

Treatment

Standard therapies

The treatment of CD is directed toward the specific symptoms that are apparent in each individual.

For localized (unicentric) disease, surgical removal of the affected lymph node(s) is usually sufficient. In some cases, ionizing radiation (radiotherapy) has proven effective.

For multicentric disease, chemotherapy and radiation had been the cornerstones of treatment, but have been largely supplanted by newer, more directed therapies. These include a drug which targets the IL-6-producing plasma cells for destruction (Rituxan®/rituximab) and drugs which either block the action of IL-6 (Actemra®/tocilizumab) or scavenge IL-6 from the bloodstream (Sylvant®/siltuximab). Additional symptomatic and supportive therapy may include corticosteroids or autologous bone marrow transplantation (used most frequently for severe disease or disease associated with POEMS syndrome).

In 2014, Sylvant® was approved to treat patients with MCD. This is the first FDA-approved drug to treat patients with MCD. Sylvant® is marketed by Janssen Biotech Inc.

Find out more about Sylvant®

Investigational therapies

Tocilizumab (Actemra®), manufactured by Roche Pharmaceuticals in the United States, has shown substantial efficacy in the treatment of CD in a small study from Japan. The drug was approved by the FDA for the treatment of Rheumatoid arthritis.

Castleman's Disease Summit

The Castleman's Disease Collaborative Network (CDCN) 'Beating Castleman's Disease Together, A Patient & Loved Ones Summit' is an opportunity for patients to gather with others affected by Castleman disease. Patients are given a unique chance to share their stories in a supportive forum, and to participate in activities aimed at furthering awareness and research. This gathering – the only one of its kind happening for Castleman disease patients – gives participants the opportunity to learn the basics about this rare disease, what resources are available, including treatment options and emotional support, and to learn about the future direction for Castleman disease research.

http://www.cdcn.org/2016-patients-loved-ones-summit

Research

There are still many unanswered questions about CD, which can make treatment difficult, such as:

  • Which cell is the problem cell (or “Castleman cell”)?
  • What cellular signaling pathways are activated?
  • What are all of the chemicals being secreted by these activated cells?

ACCELERATE is the first ever natural history research study for CD patients! If you are a patient and would like to become part of this study please follow the link below:

CDCN: ACCELERATE Patient Research Study

Links to more information about CD:

We would like to thank the Castleman Disease Collaborative Network (CDCN) for permission to reproduce some information and pictures.