iMCD is a potentially life-threatening condition that can hide in the shadows of other diseases1
Due to the overlapping symptoms and rarity of the disorder, diagnosing iMCD can be challenging1
Autoimmune1
- Rheumatoid arthritis
- Juvenile idiopathic arthritis
- Adult-onset Still disease
- Systemic lupus erythematosus
- IgG4-related disease
- Hemophagocytic lymphohistiocytosis/macrophage activation syndrome
Overlapping symptom1
- Viral hemophagocytic lymphohistiocytosis
Infectious1
- Acute Epstein-Barr virus
- Acute human immunodeficiency virus
Overlapping symptoms1
- Human herpesvirus-8 (Kaposi’s sarcoma–associated herpesvirus)
- Multicentric Castleman disease
Malignant1
- Hodgkin lymphoma
- Non-Hodgkin lymphoma
- Follicular dendritic cell sarcoma
- Polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes (POEMS) syndrome
Overlapping symptoms1
- Malignancy-associated hemophagocytic lymphohistiocytosis
- Autoimmune lymphoproliferative syndrome
-Corey Casper, MD, MPH
Patients may cycle through multiple specialists in their diagnostic journey
Patient
presents with flu-like
symptoms and
lymphadenopathy
to primary care
physician
Imaging and
laboratory tests
Patient referred
to hospital for
complications
Patients may cycle through multiple specialists in their diagnostic journey
Potential patient journeya
aThis patient journey is not a complete representation of all the doctors a patient may see in their journey to diagnosis.
Suspicion is the first step toward diagnosis of iMCD
Suspicion of iMCD should be elevated with the involvement of more than one lymph node in addition to:
involvement5,6,a
- Cytopenia
- Unexplained thrombosis
- New hematologic malignancy
dysfunction1,6,a
- Renal dysfunction/failure
- Pulmonary dysfunction
- Hepatosplenomegaly
- Solid tumors
autoimmunity1,7
- Markers of inflammation
- Symptoms of inflammation (edema, ascites)
symptoms1,8
- Flu-like symptoms
- Night sweats
- Fatigue, malaise
aStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 235 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for morbidity patterns and healthcare utilization6:
- Of the 30.7 million patients eligible for inclusion in the analysis, 487 patients were diagnosed with Castleman disease (CD) according to ICD-9/ICD-10 codes, and 271 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.6
- To prevent confounding, iMCD patients were matched with non-iMCD controls (frequency, 1:50) to analyze key morbidities and healthcare metrics (e.g., ER visits, length of hospital stays).6
- Statistical methods (e.g., Mutual Information (MI) Analysis, Welch’s Unequal Variance t-Test) were used to identify relevant features and test to understand prevalence and morbidities in patients with iMCD.
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.6
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.6
- Administrative claims data are subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2) and the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, whichever was diagnosed first between 2006 and 2020. iMCD mimics or CD subtypes other than iMCD may have been inadvertently included in this study.6
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals; therefore, results cannot be generalized to the full patient population in the US.6
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Karan Kanhai, Francis Shupo, and Rabecka Martin were employed by EUSA Pharma at the time this research was conducted. They participated in the analysis and interpretation of data and provided editorial support to the authors.6
Regardless of initial presentation, patients with iMCD may develop life-threatening complications9
Life-threatening symptoms of iMCD include:
- Increased presence of malignancy, primarily lymphoma
symptoms10
- Coma, seizures, cerebrovascular accident
- Extreme and widespread tissue swelling
failure11,13
- Leading cause of death in iMCD, including renal, pulmonary, or cardiac failure that may lead to death
Criteria from the Castleman Disease Collaborative Network (CDCN) help identify and diagnose iMCD1
- The CDCN has established evidence-based, expert consensus diagnostic criteria1
- In order to diagnose a patient with iMCD, you must ensure they meet both Major Criteria and at least 2 of the 11 Minor Criteria, including ≥1 laboratory abnormality, and rule out diseases in the Exclusion Criteria1
Major Criteria
(need both)1
Histology consistent with Castleman disease (CD)
≥2 enlarged lymph node groups
CDCN Major Criteria
Upon examination, the lymph node must have histopathologic features consistent with CD. The patient
is then sent for imaging if multiple lymph node groups are involved and MCD is suspected
(Need both)
Histopathologic lymph node features consistent
with the iMCD spectrum
Features along the spectrum include: (need grade 2 to 3
for either regressive GCs or plasmacytosis at minimum)
- Regressed/atrophic/atretic GCs, often with expanded mantle zones composed of concentric rings of lymphocytes in an “onion skinning” appearance
- FDC prominence
- Vascularity, often with prominent endothelium in the interfollicular space and vessels penetrating into the GCs with a “lollipop” appearance
- Sheetlike, polytypic plasmacytosis in the interfollicular space
- Hyperplastic GCs
Enlarged Lymph Nodes
- ≥1 cm in short-axis diameter in ≥2 lymph node stations
CD, Castleman disease; FDC, follicular dendritic cell; GCs, germinal centers; MCD, multicentric Castleman disease.
Minor Criteria (need ≥2,
with ≥1 laboratory criterion)1
- Constitutional symptoms
- Large spleen and/or liver
- Fluid accumulation
- Violaceous papules
- Lymphocytic interstitial pneumonitis
- Elevated CRP or ESR
- Anemia
- Thrombocytopenia or thrombocytosis
- Hypergammaglobulinemia
- Hypoalbuminemia
- Renal dysfunction
CDCN Minor Criteria
If the patient meets at least 2 minor criteria requirements (with at least 1 being a laboratory abnormality) for diagnosis of iMCD, disease is confirmed.
(Need ≥2 of 11 criteria with ≥1 laboratory criterion)
Laboratorya
- Elevated CRP (>10 mg/L) or ESR (>15 mm/h)b
-
Anemia (hemoglobin <12.5 g/dL for males, hemoglobin
<11.5 g/dL for females) -
Thrombocytopenia (platelet count <150 k/μL) or thrombocytosis
(platelet count >400 k/μL) - Hypoalbuminemia (albumin <3.5 g/dL)
-
Renal dysfunction (eGFR <60 mL/min/1.73 m2) or proteinuria
(total protein 150 mg/24 h or 10 mg/100 mL) -
Polyclonal hypergammaglobulinemia (total ү globulin or
immunoglobulin G >1700 mg/dL)
Clinical
-
Constitutional symptoms: night sweats, fever (>38°C), weight loss,
or fatigue (≥2 CTCAE lymphoma score for B symptoms) - Enlarged spleen and/or liver
- Fluid accumulation: edema, anasarca, ascites, or pleural effusion
- Eruptive cherry hemangiomatosis or violaceous papules
- Lymphocytic interstitial pneumonitis
CD, Castleman disease; CRP, C-reactive protein; CTCAE, Common Terminology Criteria for Adverse Events; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate.
aLaboratory cutoff thresholds are provided as guidance, but it is recognized that some laboratories have slightly different ranges. It is suggested that you use the upper and lower ranges from your particular laboratory to determine if a patient meets a particular laboratory minor criterion.
bEvaluation of CRP is mandatory and tracking CRP levels is highly recommended, but ESR will be accepted if CRP is not available.
Exclusion Criteria1
Exclude diseases that iMCD can
mimic, such as autoimmune,
malignant, and infectious diseases
CDCN Exclusion Criteria1
After excluding other diseases that can mimic iMCD, one must exclude POEMS-associated
MCD and HHV-8. If those subtypes of MCD are excluded, one must suspect iMCD.
(Must rule out each of these diseases that can mimic iMCD)
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 iMCD) -
Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or
chronic active EBV (detectable EBV viral load not necessarily exclusionary) -
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)
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Adult-onset Still disease
- Juvenile idiopathic arthritis
-
Autoimmune lymphoproliferative
syndrome
Malignant/lymphoproliferative 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
- FDC sarcoma
- POEMS syndromea
Select additional features supportive of but not
required for diagnosis
- Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or B2M
-
Reticulin fibrosis of bone marrow (particularly in patients with
TAFRO syndrome) -
Diagnosis of disorders that have been associated with iMCD:
paraneoplastic pemphigus, bronchiolitis obliterans organizing pneumonia,
autoimmune cytopenias, polyneuropathy (without diagnosing POEMSa),
glomerular nephropathy, or inflammatory myofibroblastic tumor
B2M, beta-2 microglobulin; CMV, cytomegalovirus; EBV, Epstein-Barr virus; FDC, follicular dendritic cell; HHV-8, human herpesvirus-8; HIV, human immunodeficiency virus; IgA, immunoglobulin A; IgE, immunoglobulin E; IHC, immunohistochemistry; IL-6, interleukin-6; iMCD, idiopathic multicentric Castleman disease; LANA-1, latency-associated nuclear antigen 1; LDH, lactate dehydrogenase; MCD, multicentric Castleman disease; PCR, polymerase chain reaction; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; sIL-2R, soluble interleukin-2 receptor; TAFRO, thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly; VEGF, vascular endothelial growth factor.
aPOEMS is considered to be a disease “associated” with CD. Because the monoclonal plasma cells are believed to drive the cytokine storm, the CDCN guidelines do not consider it iMCD, but rather “POEMS-associated MCD.”
CDCN Major Criteria
Upon examination, the lymph node must have histopathologic features consistent with CD. The patient
is then sent for imaging if multiple lymph node groups are involved and MCD is suspected
(Need both)
Histopathologic lymph node features consistent
with the iMCD spectrum
Features along the spectrum include: (need grade 2 to 3
for either regressive GCs or plasmacytosis at minimum)
- Regressed/atrophic/atretic GCs, often with expanded mantle zones composed of concentric rings of lymphocytes in an “onion skinning” appearance
- FDC prominence
- Vascularity, often with prominent endothelium in the interfollicular space and vessels penetrating into the GCs with a “lollipop” appearance
- Sheetlike, polytypic plasmacytosis in the interfollicular space
- Hyperplastic GCs
Enlarged Lymph Nodes
- ≥1 cm in short-axis diameter in ≥2 lymph node stations
CD, Castleman disease; FDC, follicular dendritic cell; GCs, germinal centers; MCD, multicentric Castleman disease.
CDCN Minor Criteria
If the patient meets at least 2 minor criteria requirements (with at least 1 being a laboratory abnormality) for diagnosis of iMCD, disease is confirmed.
(Need ≥2 of 11 criteria with ≥1 laboratory criterion)
Laboratorya
- Elevated CRP (>10 mg/L) or ESR (>15 mm/h)b
-
Anemia (hemoglobin <12.5 g/dL for males, hemoglobin
<11.5 g/dL for females) -
Thrombocytopenia (platelet count <150 k/μL) or thrombocytosis
(platelet count >400 k/μL) - Hypoalbuminemia (albumin <3.5 g/dL)
-
Renal dysfunction (eGFR <60 mL/min/1.73 m2) or proteinuria
(total protein 150 mg/24 h or 10 mg/100 mL) -
Polyclonal hypergammaglobulinemia (total ү globulin or
immunoglobulin G >1700 mg/dL)
Clinical
-
Constitutional symptoms: night sweats, fever (>38°C), weight loss,
or fatigue (≥2 CTCAE lymphoma score for B symptoms) - Enlarged spleen and/or liver
- Fluid accumulation: edema, anasarca, ascites, or pleural effusion
- Eruptive cherry hemangiomatosis or violaceous papules
- Lymphocytic interstitial pneumonitis
CD, Castleman disease; CRP, C-reactive protein; CTCAE, Common Terminology Criteria for Adverse Events; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate.
aLaboratory cutoff thresholds are provided as guidance, but it is recognized that some laboratories have slightly different ranges. It is suggested that you use the upper and lower ranges from your particular laboratory to determine if a patient meets a particular laboratory minor criterion.
bEvaluation of CRP is mandatory and tracking CRP levels is highly recommended, but ESR will be accepted if CRP is not available.
CDCN Exclusion Criteria1
After excluding other diseases that can mimic iMCD, one must exclude POEMS-associated
MCD and HHV-8. If those subtypes of MCD are excluded, one must suspect iMCD.
(Must rule out each of these diseases that can mimic iMCD)
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 iMCD) -
Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or
chronic active EBV (detectable EBV viral load not necessarily exclusionary) -
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)
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Adult-onset Still disease
- Juvenile idiopathic arthritis
-
Autoimmune lymphoproliferative
syndrome
Malignant/lymphoproliferative 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
- FDC sarcoma
- POEMS syndromea
Select additional features supportive of but not
required for diagnosis
- Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or B2M
-
Reticulin fibrosis of bone marrow (particularly in patients with
TAFRO syndrome) -
Diagnosis of disorders that have been associated with iMCD:
paraneoplastic pemphigus, bronchiolitis obliterans organizing pneumonia,
autoimmune cytopenias, polyneuropathy (without diagnosing POEMSd),
glomerular nephropathy, or inflammatory myofibroblastic tumor
B2M, beta-2 microglobulin; CMV, cytomegalovirus; EBV, Epstein-Barr virus; FDC, follicular dendritic cell; HHV-8, human herpesvirus-8; HIV, human immunodeficiency virus; IgA, immunoglobulin A; IgE, immunoglobulin E; IHC, immunohistochemistry; IL-6, interleukin-6; iMCD, idiopathic multicentric Castleman disease; LANA-1, latency-associated nuclear antigen 1; LDH, lactate dehydrogenase; MCD, multicentric Castleman disease; PCR, polymerase chain reaction; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; sIL-2R, soluble interleukin-2 receptor; TAFRO, thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly; VEGF, vascular endothelial growth factor.
aPOEMS is considered to be a disease “associated” with CD. Because the monoclonal plasma cells are believed to drive the cytokine storm, the CDCN guidelines do not consider it iMCD, but rather “POEMS-associated MCD.”
Methodology
The CDCN convened an international working group comprising 34 pediatric and adult hematopathology, hematology/oncology, rheumatology, immunology, and infectious diseases experts in iMCD and related disorders, including 2 physicians who are also patients with iMCD, to establish evidence-based, patient-guided, expert consensus diagnostic criteria for the treatment of iMCD. The working group reviewed clinical data from 244 iMCD cases using clinical and published data, as well as 79 cases from a randomized controlled study of siltuximab in subjects with symptomatic iMCD (NCT01024036).1
Download a detailed, print-ready version of the CDCN
Diagnostic Criteria, to help with the diagnostic process
DOWNLOAD PDF
Image courtesy of Adam Bagg, MD. Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania.
Excisional biopsies are recommended by the CDCN as the most effective way to diagnose iMCD1,12
- An excisional biopsy provides a more complete picture of the histopathological changes in an affected lymph node1,12
- Fine needle or core biopsies are unlikely to capture affected tissue and may be inadequate for accurate diagnosis12
World Health Organization (WHO) also recognizes the complexity of iMCD diagnosis13,14
Requirements for
iMCD diagnosis13
- Fulfillment of morphologic, clinical, and laboratory criteria
- Exclusion of other diseases, including HIV infection, Kaposi sarcoma herpesvirus/human herpesvirus-8 infection (KSHV/HHV-8), and other forms of Castleman disease
Histopathology13
- The histopathologic findings in iMCD are variable and non-specific, with morphologic findings showing overlap with other forms of Castleman disease15,b
Essential diagnostic criteria13
- Enlarged lymph nodes in ≥2 sites
- Lymph node morphology showing Grade 2 or 3 regressed germinal centers or plasmacytosis
- Clinical, laboratory, and exclusion criteria fulfilled
WHO Classification of iMCD: Contributors to the 5th edition of the WHO Classification of Haematolymphoid Tumors, composed of expert members in hematopathology, hematology, oncology, genetics, epidemiology, radiation oncology, immunology, and molecular biology, convened in 2021 to provide guidelines for the diagnosis and treatment of hematolymphoid tumors, including iMCD.14
bOverlapping histopathological findings may include unicentric CD, MCD-POEMS (plasma cell neoplasm with associated paraneoplastic syndrome), and KSHV/HHV-8–associated MCD.13
Clinical collaboration between physician and pathology help accelerate diagnosis and treatment plan1
Physician collaboration practices may include12:
- Providing an excisional biopsy—or full architecture—to facilitate definitive diagnosis
- Sharing full patient picture (lab values, history)
Pathology collaboration practices may include:
- Communicating and reinforcing the need for an excisional biopsy or full architecture
- Determining definite diagnosis and creating a dialogue with treating physician based on active communication and interactions, such as asking for full patient picture (i.e., lab values, definitive diagnosis) and proactively sharing full scope of analysis
-Jadee L. Neff, MD, PhD
aStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 235 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for morbidity patterns and healthcare utilization6:
-
- Of the 30.7 million patients eligible for inclusion in the analysis, 487 patients were diagnosed with Castleman disease (CD) according to ICD-9/ICD-10 codes, and 271 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.6
- To prevent confounding, iMCD patients were matched with non-iMCD controls (frequency, 1:50) to analyze key morbidities and healthcare metrics (e.g., ER visits, length of hospital stays).6
- Statistical methods (e.g., Mutual Information (MI) Analysis, Welch’s Unequal Variance t-Test) were used to identify relevant features and test to understand prevalence and morbidities in patients with iMCD.6
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.6
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.6
- Administrative claims data are subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2) and the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, whichever was diagnosed first between 2006 and 2020. iMCD mimics or CD subtypes other than iMCD may have been inadvertently included in this study.6
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals; therefore, results cannot be generalized to the full patient population in the US.6
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Karan Kanhai, Francis Shupo, and Rabecka Martin were employed by EUSA Pharma at the time this research was conducted. They participated in the analysis and interpretation of data and provided editorial support to the authors.6
References: 1. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-165. 2. Infectious disease. American College of Physicians. Accessed May 6, 2024. https://www.acponline.org/about-acp/about-internal-medicine/subspecialties-of-internal-medicine/infectious-disease. 3. Chu P, Mithu Maheswaranathan M, Neff J, et al. Case report: Is It Castleman disease, or Castleman-like? The Rheumatologist. Oct 2021. 4. Zinzani PL, Paulli M, Arcaini L, et al. Unmet clinical needs in the management of idiopathic multicentric Castleman disease: a consensus-based position paper from an ad hoc expert panel. Hemasphere. 2023;7(6):1-11. 5. Oksenhendler E, Boutboul D, Fajgenbaum D, et al. The full spectrum of Castleman disease: 273 patients studied over 20 years. Br J Haematol. 2018;180:206-216. 6. Mukherjee S, Kanhai K, Kauffman D, et al. Organ dysfunction, thrombotic events and malignancies inpatients with idiopathic multicentric Castleman disease: a population-level US health claims analysis. Leukemia. 2022;36(10):2539-2543. 7. Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353-1364. 8. van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15(9):966-974. 9. van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018;132(20):2115-2124. 10. van Rhee F, Stone K, Szmania S, Barlogie B, Singh Z. Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy. Clin Adv Hematol Oncol. 2010;8(7):486-498. 11. Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016:3(4):e163-e175. 12. Montes-Moreno S, Climent F, Fraga M, et al. Expert consensus on the integrated diagnosis of idiopathic multicentric Castleman disease. Rev Esp Patol. 2023 Jul-Sep;56(3):158-167. 13. WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [internet; beta version ahead of print]. WHO classification of tumours series, 5th ed; vol. 11. Lyon (France): International Agency for Research on Cancer;2022. Accessed July 15, 2024. https://tumourclassification.iarc.who.int/chapters/63. 14. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-1748.