Diagnostic Criteria for Idiopathic Multicentric Castleman Disease (iMCD)

Human herpesvirus-8 (HHV-8)–negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders.

Diagnostic Criteria for iMCD

I. Major Criteria (need both):
1. Histopathologic lymph node features consistent with the iMCD spectrum. Features along the iMCD spectrum include (need grade 2-3 for either regressive GCs or plasmacytosis at minimum):

• Regressed/atrophic/atretic germinal centers, often with expanded mantle zones composed of concentric rings of lymphocytes in an “onion skinning” appearance
• Follicular dendritic cell (FDC) prominence
• Vascularity, often with prominent endothelium in the interfollicluar space and vessels penetrating into the GCs with a “lollipop” appearance
• Sheetlike, polytypic plasmacytosis in the interfollicular space
• Hyperplastic GCs

2. Enlarged lymph nodes (≥1 cm in short-axis diameter) in ≥2 lymph node stations

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

Laboratory*

1. Elevated CRP (>10 mg/L) or ESR (>15 mm/h)†
2. Anemia (hemoglobin <12.5 g/dL for males, hemoglobin <11.5 g/dL for females)
3. Thrombocytopenia (platelet count <150 k/mL) or thrombocytosis (platelet count >400 k/mL)
4. Hypoalbuminemia (albumin <3.5 g/dL)
5. Renal dysfunction (eGFR <60 mL/min/1.73m2) or proteinuria (total protein 150 mg/24 h or 10 mg/100 ml)
6. Polyclonal hypergammaglobulinemia (total γ globulin or immunoglobulin G >1700 mg/dL)

Clinical

1. Constitutional symptoms: night sweats, fever (>38°C), 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

III. Exclusion Criteria (must rule out each of these diseases that can mimic iMCD)

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 iMCD)
2. Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV (detectable EBV viral load not necessarily exclusionary)
3. Inflammation and adenopathy caused by other uncontrolled infections (eg, 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

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. FDC sarcoma
5. POEMS syndrome‡

Select additional features supportive of, but not required for diagnosis

1. Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or B2M
2. Reticulin fibrosis of bone marrow (particularly in patients with trombocytopenia, anasarca/ascites, reticulin fibrosis in bone marrow, renal dysfunction, organomegaly (TAFRO))
3. Diagnosis of disorders that have been associated with iMCD: paraneoplastic pemphigus, bronchiolitis obliterans organizing pneumonia, autoimmune cytopenias, polyneuropathy (without diagnosing POEMS‡), glomerular nephropathy, inflammatory myofibroblastic tumor

B2M, b-2-microglobulin; CMV, cytomegalovirus; CTCAE, common terminology for adverse events; eGFR, estimated glomerular filtration rate; GC, germinal center; IHC, Immunohistochemistry; LANA-1, latency-associated nuclear antigen; LDH, lactate dehydrogenase; EBV, Epstein-Barr virus.
†Evaluation of CRP is mandatory and tracking CRP levels is highly recommended, but ESR will be accepted if CRP is not available.
‡POEMS is considered to be a disease “associated” with Castleman disease. Because the monoclonal plasma cells are believed to drive the cytokine storm, we do not consider it iMCD, but rather “POEMS-associated MCD.”

 

References:

1. Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, Simpson D, Liu AY, Menke D, Chandrakasan S, Lechowicz MJ, Wong RS, Pierson S, Paessler M, Rossi JF, Ide M, Ruth J, Croglio M, Suarez A, Krymskaya V, Chadburn A, Colleoni G, Nasta S, Jayanthan R, Nabel CS, Casper C, Dispenzieri A, Fosså A, Kelleher D, Kurzrock R, Voorhees P, Dogan A, Yoshizaki K, van Rhee F, Oksenhendler E, Jaffe ES, Elenitoba-Johnson KS, Lim MS. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017 Mar 23;129(12):1646-1657. [Medline]
2. Lang E, van Rhee F. Idiopathic multicentric Castleman disease: An update in diagnosis and treatment advances. Blood Rev. 2024 Mar;64:101161. [Medline]

 

Created Jul 03, 2024.