Castleman Disease Clinical Presentation

Updated: Jan 09, 2023
  • Author: Geneva E Guarin, MD, MBA; Chief Editor: Emmanuel C Besa, MD  more...
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History and Physical Examination

The four subtypes of Castleman disease can each cause a variety of signs and symptoms.

Unicentric Castleman disease (UCD) tends to have milder symptoms and rarely affects vital organs such as the liver, kidneys, and bone marrow but may present as follows:

  • Enlargement of a single lymph node or single region of lymph nodes (eg, right cervical chain), possibly with resultant compressive symptoms [13]
  • Systemic manifestations like those of human herpesvirus 8 (HHV-8)–negative/idiopathic multicentric Castleman disease (iMCD), such as flulike illness

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
  • Central nervous system symptoms
  • 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 illness (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/symptoms and laboratory features, 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 illness (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:

  • 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.
  • iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL): Thrombocytosis, hypergammaglobulinemia, and a more chronic disease course.The etiology and pathological cell types are completely unknown.

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 (BOOP)
  • Glomerular nephropathy
  • Inflammatory myofibroblastic tumor
  • Polyneuropathy (without POEMS)

The flulike signs and 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).