Castleman Disease: Symptoms, Types, Causes and Treatment

Castleman disease (CD) is a rare, complex group of disorders characterized by abnormal growth of cells in the lymph nodes and related tissues. Its perplexing nature, diverse symptoms, and evolving classification have challenged researchers and clinicians alike. In this article, we comprehensively explore the symptoms, types, causes, and treatments of Castleman disease, drawing from the latest clinical and research findings.

Symptoms of Castleman Disease

Castleman disease is notorious for its wide-ranging and often overlapping symptoms. These can vary dramatically based on the disease subtype, extent of lymph node involvement, and underlying causes. Recognizing these symptoms is crucial for early detection and appropriate management.

Symptom	Description	Prevalence/Variant	Source(s)
Lymphadenopathy	Enlarged lymph nodes, often painless	Universal	1, 6, 11
Fever	Recurrent or persistent fevers	More common in MCD	3, 6, 4
Night Sweats	Profuse sweating during sleep	Common in MCD	5, 6
Weight Loss	Unintentional, significant weight loss	Common in MCD	5, 6
Hepatosplenomegaly	Enlarged liver and/or spleen	Especially in MCD	3, 4, 6
Anemia	Low red blood cell count	Often in MCD	2, 6, 4
Fatigue	Persistent tiredness	Especially in MCD	6, 10
Skin Changes	Rash or other cutaneous manifestations	POEMS, some MCD cases	5, 1, 11
Edema/Ascites	Swelling or fluid accumulation	Severe iMCD (TAFRO)	6, 10

Table 1: Key Symptoms of Castleman Disease

Overview of Symptom Patterns

Castleman disease presents with a spectrum of symptoms that can be grouped based on whether the disease is localized (unicentric) or widespread (multicentric).

Unicentric Castleman Disease (UCD) Symptoms

• Localized lymphadenopathy: Most patients have a single, enlarged lymph node, often in the chest, neck, or abdomen.
• Asymptomatic in many cases: Many individuals experience no symptoms, and UCD is often discovered incidentally during imaging for unrelated issues.
• Mass effect symptoms: If the enlarged node compresses nearby structures, symptoms may include cough, shortness of breath, or abdominal discomfort.
• Rare systemic symptoms: Constitutional symptoms like fever or weight loss are uncommon in UCD 4, 10, 11.

Multicentric Castleman Disease (MCD) Symptoms

• Generalized lymphadenopathy: Multiple groups of lymph nodes are enlarged, often throughout the body 6, 3, 4.
• Systemic/constitutional symptoms:
  • Persistent or intermittent fever
  • Night sweats
  • Unintentional weight loss
  • Profound fatigue
• Organomegaly: Enlargement of the spleen (splenomegaly) and liver (hepatomegaly) is frequent 3, 4, 6.
• Laboratory abnormalities:
  • Anemia (low red blood cell count)
  • Elevated C-reactive protein (inflammation marker)
  • Hypergammaglobulinemia (high antibody levels)
  • Hypoalbuminemia (low blood protein)
• Edema and effusions: Severe forms—especially iMCD-TAFRO—can present with fluid accumulation (ascites), widespread swelling (anasarca), and kidney dysfunction 6, 10.
• Skin and neurological symptoms: Some patients, particularly those with POEMS syndrome, may have skin changes, nerve pain, or weakness 1, 5, 11.

Additional Notes

• Cutaneous manifestations are often under-recognized but can include rashes and other skin changes 5.
• Symptoms often fluctuate and can mimic infections, autoimmune diseases, or cancers, making diagnosis challenging 11.

Types of Castleman Disease

The classification of Castleman disease has evolved considerably. Understanding the different types is essential for accurate diagnosis, prognosis, and treatment.

Type	Description	Key Features/Variants	Source(s)
Unicentric	Single lymph node or region affected	Usually hyaline-vascular	4, 10, 15
Multicentric	Multiple lymph nodes/regions, systemic symptoms	iMCD, HHV8-MCD, POEMS	4, 10, 12
iMCD	Idiopathic, HHV8-negative	TAFRO, NOS subtypes	6, 10, 12
HHV8-MCD	Associated with human herpesvirus 8	Common in HIV+ patients	4, 10, 3
POEMS-MCD	With POEMS syndrome (polyneuropathy, etc.)	Overlaps with iMCD/MCD	1, 10, 8
Histologic	Hyaline-vascular, plasma cell, mixed variants	Relates to clinical type	7, 8, 9

Table 2: Major Types and Variants of Castleman Disease

Unicentric Castleman Disease (UCD)

• Definition: Affects a single lymph node or one region of nodes 10, 4.
• Histology: Most commonly the hyaline-vascular variant; less often plasma cell or mixed variant 7, 15.
• Clinical features: Often asymptomatic; cured with surgical excision 4, 11.
• Prognosis: Excellent, with 5-year survival rates over 90% 1.

Multicentric Castleman Disease (MCD)

• Definition: Multiple lymph node regions involved, usually with systemic symptoms and laboratory abnormalities 10, 4, 6.
• Subtypes:
  • HHV8-associated MCD (HHV8-MCD): Driven by human herpesvirus 8, often in immunosuppressed (HIV+) patients 4, 3, 10.
  • Idiopathic MCD (iMCD): HHV8-negative, cause unknown. Two main forms:
    • iMCD-TAFRO: With thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly, renal dysfunction 10, 6.
    • iMCD-NOS: Not otherwise specified; more likely to have thrombocytosis and high immunoglobulins 10.
  • POEMS-associated MCD: Accompanied by features of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) 1, 10, 8.
• Histology: More often plasma cell or mixed variant 7, 15.

Histopathological Variants

• Hyaline-vascular (HV): Most common in UCD; features abnormal, hypervascular lymphoid tissue 7, 8, 9.
• Plasma cell (PC): More often in MCD; shows sheets of plasma cells and more pronounced systemic inflammation 7, 8, 9.
• Mixed: Contains features of both HV and PC types 7, 9.

Clinical Significance

• The clinical type (unicentric vs. multicentric) typically dictates treatment and prognosis more than the histologic subtype 10, 4.
• MCD variants, especially those associated with HIV and HHV8, have distinct treatment needs and outcomes 3, 4, 10.

Causes of Castleman Disease

Castleman disease is not a single entity but a group of disorders with varied causes. Some forms have identifiable triggers, while others remain idiopathic.

Cause/Association	Details	Variant(s) Involved	Source(s)
HHV8 Infection	Human herpesvirus 8 drives disease	HHV8-MCD (often HIV+)	3, 4, 10, 15
HIV Infection	Immune suppression facilitates HHV8-MCD	HHV8-MCD	3, 4, 10
Immune Dysregulation	Faulty immunoregulation, cytokine excess	All, esp. MCD/iMCD	2, 7, 8, 9, 13
Excess IL-6	Interleukin-6 overproduction central	MCD, especially iMCD	2, 6, 13, 15, 14
Idiopathic	No identifiable cause	iMCD, many UCD cases	6, 10, 12
Autoimmunity/Paraneoplastic	Association with autoimmune disorders, POEMS, paraneoplastic pemphigus	MCD, POEMS-MCD	1, 11, 8, 15
Genetic/Unknown	Under investigation	Some iMCD, UCD	10, 7

Table 3: Causes and Associations of Castleman Disease

HHV8 and HIV: Viral Influence

• Human herpesvirus 8 (HHV8):
  • Established cause of HHV8-MCD, especially in immunosuppressed patients (notably those with HIV) 3, 4, 10.
  • Virus infects B cells, driving uncontrolled proliferation and excessive cytokine release.
• HIV infection:
  • Facilitates HHV8 infection and increases susceptibility to HHV8-MCD 3, 4.
  • HIV-associated MCD has become more common with the HIV epidemic but outcomes have improved with antiretroviral therapy 3.

Immune Dysregulation and Cytokine Storm

• Cytokine-driven disease:
  • Overproduction of interleukin-6 (IL-6) is central to the pathogenesis, especially in iMCD 2, 6, 13, 15.
  • IL-6 promotes B-cell proliferation, inflammation, and the characteristic laboratory and systemic findings 2, 13.
• Immunoregulatory deficits:
  • Faulty immune signaling leads to excessive lymphocyte and plasma cell growth 7, 8, 9.

Idiopathic and Autoimmune Links

• Idiopathic multicentric Castleman disease (iMCD):
  • No viral or other clear cause identified 6, 10, 12.
  • May be linked to subtle immune dysregulation, genetic predisposition, or unrecognized triggers.
• Autoimmune and paraneoplastic associations:
  • Some patients develop MCD in the context of autoimmune conditions, POEMS syndrome, or as a paraneoplastic (cancer-associated) phenomenon 1, 8, 11, 15.

Other Factors

• Genetic predisposition: Under investigation; not yet clearly established 10.
• Environmental/unknown triggers: Most UCD cases remain idiopathic 10, 7.

Treatment of Castleman Disease

Treatment strategies for Castleman disease are highly individualized, based on the type, severity, and underlying cause. Recent advances have improved outcomes, especially for multicentric forms.

Treatment	Indication/Type	Effectiveness/Outcome	Source(s)
Surgical Excision	Unicentric CD	Curative in most	4, 10, 15, 11
Anti-IL-6 Therapy	iMCD, some MCD	High response rates	2, 6, 12, 13, 14
Rituximab (anti-CD20)	HHV8-MCD, refractory MCD	Improved survival	3, 13, 10, 15
Antiviral Therapy	HHV8-MCD, HIV+ patients	Reduces recurrences	3, 13, 10
Corticosteroids	MCD, iMCD (initial/adjunct)	Variable, often temporary	6, 15, 12
Chemotherapy	Severe MCD, refractory iMCD	Used in combination	6, 12, 13, 15
Immunomodulators	Refractory or relapsed MCD	Thalidomide, IFN-α	15, 13, 14
Supportive Care	All types	Symptom management	6, 10

Table 4: Main Treatment Options for Castleman Disease

Treatment of Unicentric Castleman Disease (UCD)

• Surgical excision:
  • Standard of care; curative in almost all cases 4, 10, 15, 11.
  • Recurrence is rare if excision is complete.
• Radiation therapy: Occasionally used if surgery is not feasible 10, 15.
• Medical therapy: Rarely needed except in unresectable or relapsed disease.

Treatment of Multicentric Castleman Disease (MCD)

General Principles

• Systemic therapy is necessary due to widespread lymph node involvement and risk of organ failure.
• Treatment depends on subtype (HHV8-MCD, iMCD, POEMS-MCD), severity, and patient factors.

HHV8-associated MCD (HHV8-MCD)

• Rituximab: Anti-CD20 antibody, highly effective, especially in HIV+ patients 3, 13, 10, 15.
• Antiviral therapy: To control HHV8 in HIV-infected individuals 3, 13.
• Chemotherapy: Used for severe or refractory cases 3, 13, 10.
• Antiretroviral therapy: For HIV+ patients, improves immune control and outcomes 3.

Idiopathic Multicentric Castleman Disease (iMCD)

• Anti-IL-6 therapies:
  • Siltuximab (anti-IL-6) or Tocilizumab (anti-IL-6 receptor): First-line therapy, especially in severe cases; blocks the key cytokine driving disease 2, 6, 12, 13, 14.
  • High response rates, improved survival, and symptom control 12, 13.
• Corticosteroids: Used initially or as adjuncts, but responses are often temporary 6, 15, 12.
• Chemotherapy: For patients who fail anti-IL-6 therapy or present with life-threatening disease; regimens may include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) 6, 12, 13, 15.
• Other agents: Immunomodulatory drugs (e.g., thalidomide, interferon-alpha) used in refractory cases 15, 13, 14.
• Supportive care: Includes management of anemia, infections, and organ dysfunction 6, 10.

POEMS-associated MCD

• Treat underlying plasma cell disorder: Often with chemotherapy, stem cell transplantation, or targeted therapies 1, 10.
• Multidisciplinary care is essential due to multisystem involvement.

Prognosis and Follow-Up

• UCD: Excellent prognosis after complete excision, >90% 5-year survival 1, 4.
• MCD: Prognosis varies with subtype and response to therapy. HHV8-MCD and severe iMCD historically had poor outcomes, but advances in therapy have significantly improved survival 3, 6, 12, 13.
• Risk of malignancy: Patients with CD—especially MCD—are at increased risk for lymphoma and other cancers; regular follow-up is recommended 6, 9, 15.

Conclusion

Castleman disease is a rare, multifaceted group of lymphoproliferative disorders with wide-ranging symptoms, diverse types, and evolving treatment approaches. Early recognition and accurate classification are pivotal for effective management and improved outcomes.

Key Points:

• Castleman disease symptoms range from asymptomatic lymphadenopathy to severe systemic illness, depending largely on the subtype.
• The disease is classified into unicentric (localized) and multicentric (generalized) forms, with further subdivisions based on histology and underlying causes.
• Causes include viral infections (HHV8, HIV), immune dysregulation with excess IL-6, and idiopathic or autoimmune associations.
• Treatment is tailored to the subtype: UCD is curable with surgery; MCD requires systemic therapy, often with anti-IL-6 agents, rituximab, antivirals, and/or chemotherapy.
• Advances in therapy have markedly improved outcomes, but ongoing research and multidisciplinary care remain essential for optimal patient management.

Castleman disease remains a "great mimic," but increased awareness, precise classification, and targeted treatments offer hope for better prognosis and quality of life for affected individuals.