Rare Disease Report

Diagnostic Guidelines for Castleman Disease

JANUARY 22, 2017
James Radke
Castleman disease is a rare complex disease. The disease can be unicentric or multicentric, and the mulitcentric may or may not be associated with Human Herpesvirus-8 (HHV-8).
 
Castleman disease is not a cancer but is very similar to a lymphoma in that there is an abnormal growth of cells in the lymph system.
 
In unicentric Castleman disease, the abnormal growth is limited to one group of lymph nodes and can usually be treated surgically.
 
Muticentric Castleman disease involves more than one group of lymph nodes and as one would suspect, the symptoms vary greatly between patients and can mimic numerous other conditions that make it a difficult condition to diagnosis difficult.
 
And a delay in diagnosis can be deadly. Castleman disease patient (and doctor) David Fajgenbaum said that “It took 11 weeks for me to be diagnosed with idiopathic multicentric Castleman disease, and if it took 11 weeks and 1 day, I probably wouldn't have survived.”

Diagnostic Guidelines Published

Based on his experience, Fajgenbaum has spent the past few years organizing patients, clinicians, and researchers to better understand this complex condition and part of that process is to establish specific diagnostic criteria for the condition so that others will get their rare disease treated sooner.  To that end, Fajgenbaum and colleagues have published in the journal, Blood, the diagnostic criteria for diagnosing Castleman disease – more specifically, human herpesvirus-8-negative/idiopathic multicentric Castleman disease.
 
Idiopathic multicentric Castleman disease accounts for one-third to one-half of all cases of multicentric Castleman disease (the rest is HHV-8 positive).
 
Since an accurate diagnosis is challenging, as no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders, an international working group of 34 pediatric and adult pathology and clinical experts gathered to establish diagnostic guidelines for this rare condition.
 
After reviewing 244 cases, meeting twice, and refining their diagnostic criteria over a 15 month period, the panel came up with the following diagnostic criteria for idiopathic multicentric Castleman disease.

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 rile 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

 
Readers are strongly encouraged to read the paper in its entirely at Blood.

Reference

Fajgenbaum 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 


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