Castleman Disease Clinical Presentation

Updated: Nov 24, 2021
  • Author: Geneva E Guarin, MD, MBA; Chief Editor: Emmanuel C Besa, MD  more...
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History and Physical Examination

The three types of Castleman disease can each cause a variety of signs and symptoms.

Unicentric Castleman disease (UCD) is generally asymptomatic but may present as follows:

  • Localized lymphadenopathy with resultant compressive symptoms [13] : common sites are chest, neck, abdomen, and retroperitoneum; less common sites are axilla, groin, and pelvis
  • Systemic manifestations like those of human herpesvirus 8 (HHV-8)–negative/idiopathic multicentric Castleman disease (iMCD)

The presentation of multicentric Castleman disease spans a wide spectrum of severity, from mild symptoms to life-threatening organ failure. The National Comprehensive Cancer Network (NCCN) criteria for active disease include fever, C-reactive protein > 20 mg/L in the absence of other causes, and 3 or more of the following [14] :

  • Peripheral lymphadenopathy
  • Splenomegaly
  • Edema
  • Pleural effusion
  • Ascites
  • Cough
  • Nasal obstruction
  • Xerostomia
  • Rash
  • Jaundice
  • Autoimmune hemolytic anemia

HHV-8–associated multicentric Castleman disease (HHV-8–associated MCD) involves multicentric lymphadenopathy with characteristic "CD-like" lymph node histopathology and/or the following systemic manifestations, although some cases (< 10%) are asymptomatic:

  • Flulike symptoms (fever, night sweats that soak the sheets, weight loss, loss of appetite, weakness, fatigue)
  • Shortness of breath, cough
  • Nausea and vomiting
  • Numbness and weakness (neuropathy)
  • Leg edema
  • Skin rashes
  • Hemangiomata

For idiopathic multicentric Castleman disease (iMCD), according to the Castleman Disease Collaborative Network (CDCN), at least 2 of following must be present for it to be classified as severe  [15] :

  • Eastern Cooperative Oncology Group (ECOG) performance status 2 or above
  • Stage IV kidney dysfunction (estimated glomerular filtration rate < 30 mL/minute/1.73m 2, creatinine > 3 mg/dL)
  • Anasarca and/or ascites, pleural effusion, or pericardial effusion
  • Hemoglobin ≤8 g/dL
  • Pulmonary involvement/interstitial pneumonitis with dyspnea

IMCD involves multicentric lymphadenopathy with characteristic "CD-like" lymph node histopathology and a number of signs and symptoms as defined by the 2017 International Consensus Diagnostic Criteria of iMCD, which may progress or remit/relapse over time:

  • Elevated C-reactive protein (CRP) level and/or erythrocyte sedimentation rate (ESR)
  • Anemia
  • Thrombocytopenia or thrombocytosis
  • Hypoalbuminemia
  • Kidney dysfunction and/or proteinuria
  • Polyclonal hypergammaglobulinemia
  • Flulike signs and symptoms (night sweats, fever, weight loss, fatigue)
  • Large liver and/or spleen
  • Fluid accumulation (edema, anasarca, ascites, pleural effusion)
  • Eruptive cherry hemangiomatosis or violaceous papules
  • Lymphocytic interstitial pneumonitis

There are at least three subtypes of iMCD that demonstrate varying clinical features:

  • POEMS-associated, HHV-8–negative MCD: When POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell proliferative disorder, and skin changes) syndrome co-occurs with HHV-8–negative MCD, these patients often have unique clinical features and require treatment targeted at controlling the POEMS.
  • TAFRO syndrome, HHV-8–negative MCD (iMCD-TAFRO): Patients will sometimes present with thrombocytopenia, anasarca, myelofibrosis, kidney dysfunction, and organomegaly (TAFRO) without hypergammaglobulinemia. These cases often have mixed or hypervascular (formerly called hyaline vascular) histopathological features and normal gamma globulin levels.
  • Not otherwise specified (NOS), HHV-8–negative/idiopathic MCD (iMCD-NOS): HHV-8–negative MCD patients, who do not have POEMS syndrome or the TAFRO subtype, are classified as having iMCD-NOS. These patients often have thrombocytosis, less severe fluid accumulation, hypergammaglobulinemia, and mixed or plasmacytic histopathological features.

Other conditions that can co-occur with iMCD include the following:

  • Amyloidosis, a condition in which abnormal proteins build up in tissues around the body, can occur in Castleman disease. This can lead to kidney damage; heart damage; nerve damage; and intestinal problems, mainly diarrhea. If the Castleman disease is treated successfully, the amyloidosis may improve or disappear.
  • Autoimmune disease
  • Autoimmune cytopenias such as hemolytic anemia and immune thrombocytopenia (ITP)
  • Bronchiolitis obliterans organizing pneumonia
  • Glomerular nephropathy
  • Inflammatory myofibroblastic tumor
  • Polyneuropathy (without POEMS)

The flulike symptoms and acute-phase reaction, with elevation of the ESR and CRP level, elevated fibrinogen, thrombocytosis, and hypergammaglobinemia in HHV-8–associated MCD and iMCD, are believed to be driven by overproduction of interleukin-6 (IL-6).