What is iMCD

Understanding Castleman Disease and Its Subtypes

Castleman disease (CD) describes a group of distinct, nonmalignant lymphoproliferative disorders with a shared histopathology. Classification is based on the number of regions of enlarged lymph nodes and the presence or absence of human herpesvirus-8 (HHV-8).1

There are 2 main types of CD1,2:

Unicentric Castleman disease (UCD)1,2

UCD involves a single group of lymph nodes anywhere in the body that can be treated with surgical removal.

Multicentric Castleman disease (MCD)1,2

MCD affects multiple groups of lymph nodes throughout the body.

There are 2 known types:

  • HHV–8–positive MCD, which can cause Kaposi’s sarcoma—a rare cancer in which lesions grow on the skin, mouth, nose, throat, and other parts of the body
  • Human immunodeficiency virus (HIV) and HHV–8–negative MCD, also known as idiopathic multicentric Castleman disease (iMCD)
Idiopathic multicentric Castleman disease (iMCD)

iMCD is rare and can occur at any age, resulting from a cytokine storm that is often driven by interleukin‑6 (IL‑6).2,3

Unicentric Castleman disease Multicentric Castleman disease
Idiopathic multicentric Castleman disease (iMCD)

iMCD is rare and can occur at any age, resulting from a cytokine storm that is often driven by interleukin-6 (IL-6).2,3

line graph diagram

Did you know?

line graph diagram

Castleman disease incidence is in line with that of amyotrophic lateral sclerosis (ALS) and cystic fibrosis (CF).4-6

There are approximately 30,000 Americans afflicted with one of the types of Castleman disease, which is roughly the same number as ALS and CF. Every year, 500 to 1000 patients in the United States are diagnosed with new cases of iMCD.3,7-9

Clinical Presentation

iMCD Can Be Challenging to Diagnose

iMCD can mimic other autoimmune, malignant, and inflammatory disorders. Its symptoms can overlap with those of acute human immunodeficiency virus (HIV), non-Hodgkin lymphoma, lupus, or other rare malignant and nonmalignant disorders. The following graphic highlights just some of the different diseases that share symptoms or characteristics with iMCD.3

Venn diagram explaining how idiopathic multicentric Castleman disease, or iMCD, can be confused for autoimmune conditions, infections, and malignancies. Expanded state.
Overlapping symptoms3,12,13

Fever, night sweats, weight loss, enlarged or swollen lymph nodes, fatigue

malignancy
Overlapping symptoms3,10,11

Fatigue, fever, swollen glands

AUTOIMMUNE
Overlapping symptoms3,14

Fever, loss of appetite, and swollen lymph nodes, most often in the neck and armpit

infection

iMCD Can Vary in Clinical Presentation

Symptoms can range from mild to life-threatening.8,9 Some of the common clinical symptoms of iMCD include the following2,3,8:

Graphic showing various symptoms observed in patients with idiopathic multicentric Castleman disease.
Generalized Lymphadenopathy

Enlargement seen across multiple groups of lymph nodes

Fluid Accumulation

Edema, ascites, and/or other symptoms of fluid overload

Flu-like Symptoms

Fevers, night sweats, fatigue, and weight loss

Organomegaly

Enlarged liver or spleen

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Diagnosis

Consensus Diagnostic Criteria for iMCD

Until recently, there were no diagnostic or treatment criteria for iMCD, which led to a delay in diagnosis and poor patient outcomes. In 2018, the Castleman Disease Collaborative Network (CDCN) convened a working group of 42 international experts that established the first evidence-based consensus treatment guidelines for iMCD, based on a review of 344 cases and expert opinion. Below are some highlights from the recent CDCN guidelines that can help achieve an accurate diagnosis.9

  • Major Criteria3

    Upon examination, the lymph node must have histopathologic features consistent with Castleman disease.

    The patient is then sent for imaging if multiple lymph node groups are involved and iMCD is suspected.

  • Minor Criteria3

    Patients must meet at least 2 of 11 minor criteria, such as the presence of constitutional symptoms or presence of an enlarged liver or spleen.

    At least 1 of the criteria must be a laboratory abnormality such as elevated C-reactive protein (CRP) or anemia.

  • Exclusion Criteria3

    “Castleman-like” histopathologic changes and clinical abnormalities may be present in several malignant, infectious, and autoimmune conditions and should be excluded.

    The presence of human herpesvirus-8 (HHV-8) must
    also be excluded.

You can download a detailed, print-ready version of the CDCN Diagnostic Criteria, which includes a checklist that can help you during the diagnostic process.

Download CDCN Diagnostic Criteria

An Excisional Biopsy Ensures Pathologic Confirmation

Understanding the difference between an incisional biopsy and an excisional biopsy is crucial to confirm the presence of abnormal histology in patients with iMCD. Here is why an excisional biopsy is so important:

Incisional (Core) Biopsy

During this procedure, a needle core is used to extract only a small part of the lymph node. Because the pathologic diagnosis of iMCD requires examination of the total lymph node architecture, incisional (core) biopsies may be inadequate, as they are unlikely to capture the tissue of the affected area. The findings will most likely be nonspecific or appear reactive in nature.15,16

Excisional Biopsy

An excisional biopsy, involving complete removal of an overgrown lymph node by making a surgical incision, allows examination of the total lymph node architecture.17

Pull down to reveal core biopsy
Graphic showing needle core biopsy, also known as incisional biopsy, may not be enough to confirm idiopathic multicentric Castleman disease.
Graphic showing needle core biopsy, also known as incisional biopsy, may not be enough to confirm idiopathic multicentric Castleman disease.
biopsy details
Regressed Germinal Center
biopsy detail #1
Regressed Germinal Center
biopsy detail
Regressed Germinal Center

Did you know?

Excisional biopsy is strongly recommended and may be the only definitive way to confirm diagnosis of iMCD.3

person magnifine glass

Did you know?

Excisional biopsy is strongly recommended and may be the only definitive way to confirm diagnosis of iMCD.3

person with magnifine glass

Subtypes of iMCD Based on Clinical Features

Some patients with iMCD present with an intense inflammatory syndrome characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO). iMCD-TAFRO is associated with hypervascular or mixed lymph node histopathology and normal gamma globulin levels.2,8

The majority of patients with iMCD, however, present with a subtype that is not otherwise specified (NOS) and is characterized by a less intense inflammatory syndrome, normal-to-elevated platelet counts, plasmacytic or mixed lymph node histopathology, and polyclonal hypergammaglobulinemia.2,8

Patients with iMCD should be further subdivided into having iMCD-TAFRO or iMCD-NOS on the basis of clinical features.2

iMCD-TAFRO2,8
~20% of cases 		iMCD-NOS2,8
~80% of cases
Inflammatory syndrome Intense inflammatory syndrome characterized by Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis/renal dysfunction, Organomegaly Less intense inflammatory syndrome
Platelet count Thrombocytopenia/low level of platelets Normal/elevated platelet counts
Histopathology Hypervascular or mixed lymph node Plasmacytic or mixed lymph node
Gamma globulin levels Normal gamma globulin levels Elevated gamma globulin levels
iMCD cases8 ~80%iMCD-NOS ~20%iMCD-TAFRO

Did you know?

iMCD can present across a histopathologic spectrum, ranging from hypervascular to plasmacytic pathology.2

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References:

  1. American Cancer Society. What is Castleman disease? https://www.cancer.org/cancer/castleman-disease/about/what-is-castleman-disease.html. Revised February 1, 2018. Accessed November 20, 2019.

  2. Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330.

  3. 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):1646-1657.

  4. Walling AD. Amyotrophic lateral sclerosis: Lou Gehrig’s disease. Am Fam Physician. 1999;59(6):1489-1496.

  5. Mumcuoğlu EU, Long FR, Castile RG, Gurcan MN. Image analysis for cystic fibrosis: computer-assisted airway wall and vessel measurements from low-dose, limited scan lung CT images. J Digit Imaging. 2013;26(1):82-96.

  6. Cystic Fibrosis Foundation. About cystic fibrosis. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed August 26, 2020.

  7. Munshi N, Mehra M, van de Velde H, Desai A, Potluri R, Vermeulen J. Use of a claims database to characterize and estimate the incidence rate for Castleman disease. Leuk Lymphoma. 2015;56(5):1252-1260.

  8. Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-e175.

  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. Shanbhag S, Ambinder RF. Hodgkin lymphoma: a review and update on recent progress. CA Cancer J Clin. 2018;68(2):116-132.

  11. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.

  12. Fugl A, Andersen CL. Epstein-Barr virus and its association with disease - a review of relevance to general practice. BMC Fam Pract. 2019;20(1):62.

  13. Parekh BS, Ou CY, Fonjungo PN, et al. Diagnosis of human immunodeficiency virus infection. Clin Microbiol Rev. 2018;32(1):e00064-18.

  14. Mahmud SA, Binstadt BA. Autoantibodies in the pathogenesis, diagnosis, and prognosis of juvenile idiopathic arthritis. Front Immunol. 2019;9:3168.

  15. American Cancer Society. Tests for Castleman disease. https://www.cancer.org/ cancer/castleman-disease/detection-diagnosis-staging/diagnosis.html. Revised February 2, 2018. Accessed November 20, 2019.

  16. Bonekamp D, Horton KM, Hruban RH, Fishman EK. Castleman disease: the great mimic. Radiographics. 2011;31(6):1793-1807.

  17. Allin D, David S, Jacob A, Mir N, Giles A, Gibbins N. Use of core biopsy in diagnosing cervical lymphadenopathy: a viable alternative to surgical excisional biopsy of lymph nodes? Ann R Coll Surg Engl. 2017;99(3):242-244.

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