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:
UCD involves a single group of lymph nodes anywhere in the body that can be treated with surgical removal.
MCD affects multiple groups of lymph nodes throughout the body.
There are 2 known types:
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
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
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
Fever, night sweats, weight loss, enlarged or swollen lymph nodes, fatigue
Fatigue, fever, swollen glands
Fever, loss of appetite, and swollen lymph nodes, most often in the neck and armpit
Symptoms can range from mild to life-threatening.8,9 Some of the common clinical symptoms of iMCD include the following2,3,8:
Enlargement seen across multiple groups of lymph nodes
Edema, ascites, and/or other symptoms of fluid overload
Fevers, night sweats, fatigue, and weight loss
Enlarged liver or spleen
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
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.
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.
“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 CriteriaUnderstanding 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:
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
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
Excisional biopsy is strongly recommended and may be the only definitive way to confirm diagnosis of iMCD.3
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 can present across a histopathologic spectrum, ranging from hypervascular to plasmacytic pathology.2
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.
Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330.
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.
Walling AD. Amyotrophic lateral sclerosis: Lou Gehrig’s disease. Am Fam Physician. 1999;59(6):1489-1496.
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.
Cystic Fibrosis Foundation. About cystic fibrosis. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed August 26, 2020.
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.
Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-e175.
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.
Shanbhag S, Ambinder RF. Hodgkin lymphoma: a review and update on recent progress. CA Cancer J Clin. 2018;68(2):116-132.
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.
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.
Parekh BS, Ou CY, Fonjungo PN, et al. Diagnosis of human immunodeficiency virus infection. Clin Microbiol Rev. 2018;32(1):e00064-18.
Mahmud SA, Binstadt BA. Autoantibodies in the pathogenesis, diagnosis, and prognosis of juvenile idiopathic arthritis. Front Immunol. 2019;9:3168.
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.
Bonekamp D, Horton KM, Hruban RH, Fishman EK. Castleman disease: the great mimic. Radiographics. 2011;31(6):1793-1807.
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.
SYLVANT® (siltuximab) is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.
Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.
Do not administer SYLVANT to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving SYLVANT closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.
Do not administer live vaccines to patients receiving SYLVANT because IL-6 inhibition may interfere with the normal immune response to new antigens.
Stop the infusion of SYLVANT if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT.
Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions.
Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
Gastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.
The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infections.
Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of SYLVANT on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).
Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in the Prescribing Information are not met, consider delaying treatment with SYLVANT. Do not reduce dose.
Do not administer SYLVANT to patients with severe infections until the infection resolves.
Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
Please see full Prescribing Information for additional important safety information.
SYLVANT® (siltuximab) is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.
Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.
Do not administer SYLVANT to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving SYLVANT closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.
Do not administer live vaccines to patients receiving SYLVANT because IL-6 inhibition may interfere with the normal immune response to new antigens.
Stop the infusion of SYLVANT if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT.
Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions.
Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
Gastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.
The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infections.
Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of SYLVANT on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).
Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in the Prescribing Information are not met, consider delaying treatment with SYLVANT. Do not reduce dose.
Do not administer SYLVANT to patients with severe infections until the infection resolves.
Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
Please see full Prescribing Information for additional important safety information.
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