CD lymph node

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.

The immune system attacks vital organs

Castleman disease (CD) describes a group of three heterogeneous inflammatory disorders that all share a 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. The immue system's normal response to fighting off an infection is inflammation. Lymph nodes are the home base for immune cells. In CD patients, inflammatory cells become hyper-activated and produce excess molecules (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. 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.

A wide-ranging disease that is difficult to diagnose

subtypes

Castleman disease is first classified based on the number of lymph node(s) or regions that are affected - unicentric CD (UCD) versus multicentric CD (MCD). 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). 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 the symptoms and laboratory test results common to MCD, is diagnosed with Multicentric Castleman Disease (MCD). In short, when CD features are identified by a pathologist under the microscope, the patient is diagnosed based on number and location of affected lymph node(s) or regions.

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), he/she 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). 

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). The largest published study of TAFRO can be found here.

To make things more complex the 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). 

Symptom severity differs greatly amond CD patient and can range from relatively asymptomatic to life-threatening multi-organ failure (e.g. kidney, liver, bone marrow, heart, lung failure). It is very important to understand the exact subtype of CD that you have (UCD, HHV-8-associated MCD, iMCD with TAFRO, iMCD not with TAFRO), because each subtype can require different treatment approaches.

 

Unicentric Castleman disease

(UCD)

HHV-8-associated Multicentric CD -

(HHV-8+MCD)

Idiopathic Multicentric Castleman disease (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)

The driver of the disease is 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 – We need your help to find it

None – We need your help to find it

5-year Survival Rate

90% - 1 in 10 die

62% - 1 in 3 die, but new data shows patients treated with rituximab have a 90% 5-year survival rate

62% - 1 in 3 die

MCD is as deadly as cancer

Patients are commonly misdiagnosed with other illnesses or told they have cancer before being correctly diagnosed with Castleman disease. Many patients are relieved to find out they do not have cancer, but Multicentric Castleman disease has a nearly identical 5-year mortality rate as colon cancer (35%) and a worse mortality rate than prostate cancer, breast cancer, non-Hodgkin lymphoma, and Hodgkin lymphoma. Multicentric Castleman disease is also often treated with chemotherapy that is also used for cancer.

Not that rare: As common as ALS

Recent estimates suggest the incidence of all subtypes of Castleman disease (UCD, HHV-8-associated MCD, and iMCD) to be approximately 6,500 to 7,700 new cases per year in the US. Multicentric Castleman disease is estimated to account for one in four Castleman disease cases. The disease can occur in males and females at any age, including young children, but UCD is more common in 20-30 year olds; MCD is most common in 40-60 year olds.

While it does not garner the same public awareness as Lou Gehrig's Disease (ALS), just as many Americans are facing this grim disease. ALS has an incidence of 5,600 per year in the US (http://www.alsa.org/about-als/facts-you-should-know.html).

ALS and CD

Cancer Risk

Hematologic malignancies are diagnosed at an increased frequency within 2 years of iMCD diagnosis. These malignant cells may have been present all along and actually secreted the IL-6 that was responsible for the preceding iMCD symptoms and diagnosis.  Alternative explanations for the frequent association between iMCD and malignancy include the possibility that iMCD is a "pre-lymphoma" that eventually transforms; excessive cytokine release promotes malignant transformation; iMCD treatments cause or increase susceptibility to secondary malignancies; or an unidentified virus may be responsible for both the iMCD and the malignancy. We suggest that a search for an underlying malignancy be conducted in all newly diagnosed iMCD patients. Further research is needed to better understand the relationship between iMCD and malignancies.

Signs & Symptoms

S and S CD

The clinical spectrum of disease severity is very broad. It ranges from gradual enlargement of lymph nodes with mild symptoms (unicentric CD) to the sudden, intense onset of several of the following systemic symptoms that can be seen with multicentric CD:

  • Fever: 26-52% of iMCD patients were reported to have this symptom1 
  • Night sweats:10-62% of iMCD patients were reported to have this symptom1 
  • Loss of appetite, nausea, and vomiting
  • Unintended weight loss: 16-72% of iMCD patients were reported to have this symptom1
  • Weakness and fatigue
  • Enlarged liver or spleen: 41-78% of iMCD patients were reported to have this symptom1
  • Peripheral neuropathy (numbness in the hands and feet)
  • Eruption of cherry hemangiomas (benign proliferations of blood vessels) on the skin
  • Edema (swelling), ascites (fluid accumulation in the abdomen), and/or other symptoms of fluid overload: 23-78% of iMCD patients were reported to have this symptom1 
  • Decreased urine output and systemic toxicity due to kidney failure
  • Bruising, easy bleeding, and risk of infection due to bone marrow failure

Individuals with MCD will often demonstrate several of the following abnormal laboratory values:

  • Elevated erythrocyte sedimentation rate (ESR): 34-92% of iMCD patients were reported to have this laboratory abnormality1
  • Elevated C-reactive protein (CRP): 51-82% of iMCD patients were reported to have this laboratory abnormality1
  • Elevated fibrinogen
  • Low hemoglobin (anemia): 62-87% of iMCD patients were reported to have this laboratory abnormality1
  • Low platelet count (thrombocytopenia): 22-44% of iMCD patients were reported to have this laboratory abnormality1
  • Elevated creatinine and BUN, proteinuria: 9-71% of iMCD patients were reported to have high creatinine or high BUN1
  • Low albumin: 45-90% of iMCD patients were reported to have this laboratory abnormality1
  • Polyclonal lymphocytes 
  • Elevated IL-6: 45-90% of iMCD patients were reported to have this laboratory abnormality1
  • Elevated VEGF: 13-80% of iMCD patients were reported to have this laboratory abnormality1
  • Autoimmune antibodies, such as positive anti-nuclear antibody, anti-erythrocyte autoantibodies, and anti-platelet antibodies: 9-71% of iMCD patients were reported to have a positive Coombs testand 12-37% of iMCD patients were reported to have positive ANA test1
  • Hypergammaglobulinemia: 49-77% of iMCD patients were reported to have this laboratory abnormality1

Reference: 1 Liu, A. Y., Nabel, C. S., Finkelman, B. S., Ruth, J. R., Kurzrock, R., van Rhee, F., ... & Fajgenbaum, D. C. (2016). Idiopathic multicentric Castleman's disease: a systematic literature review. The Lancet Haematology3(4), e163-e175.

CD lymph nodes demonstrate several characteristics, which can be divided into one of four variants: hyaline-vascular (HV), plasma cell (PC), mixed, and plasmablastic.

HV is characterized by widened mantle zones composed of concentric rings of small lymphocytes in an “onion skin” pattern around small atrophic germinal centers with penetrating hyalinized vessels and dysplastic follicular dendritic cells (FDCs). In PC, the germinal centers are hyperplastic rather than atrophic, the interfollicular region contains sheets of plasma cells and vascular proliferations, the FDC network is normal, and there is preserved lymph node architecture. The mixed variant displays features of both HV and PC. The plasmablastic variant is only found in HHV-8-associated MCD.

The reliability and significance of these variants is unclear, as there are reports of transitions between HV and PC variants on subsequent biopsies, as well as the simultaneous presence of both types at separate sites within the same patient.

Raj Jayanthan, CDCN Director of Patient Engagement, describes his experience as a patient:

 

Diagnosis

It can be difficult for physicians to diagnose Castleman disease - particularly UCD and HHV-8-associated MCD - because there are no official diagnostic criteria and no definitive tests. It can take anywhere from a few days to many years to diagnose CD. Additionally, CD symptoms can be similar to those of other conditions so multiple tests must be conducted in order to rule out other possibilities. Publication of the first-ever International Diagnostic Criteria for HHV-8-negative/idiopathic MCD in January 2017 has helped to shorten the time until diagnosis for iMCD patients. 

Regardless of the subtype, all patients require a lymph node biopsy. The biopsy may involve sticking a needle into the lymph node or surgically removing enlarged lymph node(s). From there, a pathologist examines the structure of the lymph node tissue under the microscope and compares its histological features to that of other possible diseases. A diagnosis of CD is made when the pathologist confirms the lymph node shows histological features of CD under the microscope. The histological features of CD include "atrophic germinal centers," "widened mantle zones," "onion-skinning," "increased vascularity," "lollipop sign," "follicular dendritic cell prominence," and "increased plasma cells" - each of these features can be seen in normal lymph nodes and individuals with other diseases; it is the constellation of multiple features that suggests a patient may have CD. Per above, the review of the lymph node is the first step. Then, you need to be assessed for how many regions of enlarged lymph nodes you have (1 region: unicentric or >1 region: multicentric). If multicentric, you should be tested for HHV-8. If HHV-8-negative, you should be evaluated for the TAFRO clinical subtype. 

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

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. Please click here to use our HHV-8-negative/"idiopathic" multicentric Castleman disease Diagnostic Calculator. The Diagnostic Calculator can be used to determine if the disease features present in a patient are consistent with a diagnosis of idiopathic multicentric Castleman disease using the international, evidence-based consensus diagnostic criteria. However, please note that the Diagnostic Calculator is provided as an informational resource only and is not to be used or relied on for any diagnostic or treatment purposes.

Major Diagnostic Criteria (need both present to diagnose)

  1. 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 

  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

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

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

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

  4. Hypoalbuminemia (albumin less than 3.5g/dL) 

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

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


Clinical

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

  2. Large spleen and/or liver 

  3. Fluid accumulation: edema, anasarca, ascites, or pleural effusion 

  4. Eruptive cherry hemangiomatosis or violaceous papules 

  5. 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:

  1. 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) 

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

  3. 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):

  1. Systemic lupus erythematosus 

  2. Rheumatoid arthritis 

  3. Adult-onset Still disease 

  4. Juvenile idiopathic arthritis 

  5. Autoimmune lymphoproliferative syndrome (ALPS) 
 

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

  1. Lymphoma (Hodgkin and non-Hodgkin) 

  2. Multiple myeloma 

  3. Primary lymph node plasmacytoma 

  4. Follicular dendritic cell sarcoma 

  5. POEMS syndrome


Reference

Readers are strongly encouraged to read the paper in its entirely at BloodFajgenbaum DC, Uldrick TS, Bagg A, et al.  International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. Published online January 13, 2017; doi:10.1182/blood-2016-10-746933 

No official criteria exists for diagnosing UCD or HHV-8-associated MCD.

Diagnosis is further complicated by the fact that several disorders are reported to occur simultaneously with CD, which may or may not be responsible for the CD. A list of these is provided below.

Neoplastic Inflammatory Infectious
POEMS Syndrome

Adult Onset Still’s Disease

Human Herpes Virus 6
Paraneoplastic Pemphigus Systemic Juvenile Idiopathic Arthritis Hepatitis B Virus
Melanoma Sarcoidosis Toxoplasma
Angioimmunoblastic T-cell Lymphoma Amyloidosis Mycobacterium Tuberculosis
Indolent T-Lymphoblastic Proliferation Pure Red Cell Aplasia Cytomegalovirus
Inflammatory Hepatocellular Adenoma Acquired Factor VIII Deficiency Toxoplasma
  Myasthenia Gravis

 

  Familial Mediterranean Fever  
  Glomerulonephritides  

Dr. Ahmet Dogan presents Castleman Disease Pathology & Diagnosis at a recent ASH meeting:

Causes

pathway-top

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).

In all healthy individuals, cytokines, such as IL-6, are used by the immune system to fight infections and maintain immune system health. However, when too many cytokines, such as IL-6, are released (hypercytokinemia), these cytokines are damaging to organs and inflammatory cells are signaled to replicate quickly.

Idiopathic MCD (iMCD) patients also exhibit high cytokine levels, such as IL-6, but the cause of the cytokine release is not known. Fajgenbaum, van Rhee, and Nabel recently proposed that iMCD represents a common end point that can be reached through multiple processes, each involving immune dysregulation and a common pathway of elevated proinflammatory cytokine release. They hypothesize that one or more of the following three candidate processes are responsible for driving iMCD hypercytokinemia: (1) autoimmune/autoinflammatory mechanisms via autoantibody antigenic stimulation or a germ-line genetic aberration in innate immune regulation (systemic inflammatory disease hypothesis), (2) ectopic cytokine secretion by malignant or benign tumor cells within the lymph nodes or extranodal (paraneoplastic syndrome hypothesis), and (3) viral signaling by a non-HHV-8 virus (virally driven hypothesis).

Treatment

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-negative/idiopathic Multicentric Castleman disease (iMCD): The first-ever treatment guidelines for iMCD were published in the journal Blood in 2018. 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.

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.

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. See Dispenzieri, 2017 for more information.

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.

mortality CD

New Framework

Before the CDCN, the medical community believed that 'benign lymph node tumors’ secreted Interleukin-6 (IL-6), which caused the activated immune system and organ dysfunction seen in MCD. When we combined experiences by the CDCN community from hundreds of unpublished iMCD cases with the published literature for iMCD and HHV-8-associated MCD, a potential new model disease framework emerged. Our new framework suggests that the enlarged lymph nodes are not IL-6-secreting “tumors” but are actually caused by the excess IL-6 and other proinflammatory proteins produced by an activated immune system. In essence, what we used to think was the cause (enlarged lymph node) is actually an effect and now we're trying to figure out the cause. Importantly, we now think about MCD as a hyperinflammatory disorder instead of a benign lymphoproliferative disorder.

Dr. David Fajgenbaum, co-founder & Executive Director of the CDCN, addressed the Wharton Health Care Business Conference on a new framework for Castleman disease:

We are blazing a path to a cure

There are many unanswered questions about Castleman disease, which make treatment difficult. In fact, researchers and physicians do NOT yet know:

  • 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?


With experts from around the globe working together and a community of patients fighting back, we can answer these questions and stomp out this disease.