Introduction

Castleman's disease (CD) is also known as angiofollicular lymph node hyperplasia. It is a rare lymphoproliferative disorder of young adults. The median age at the time of presentation is 35-years.

Classification

Castleman's disease (CD) is classified based on the anatomical location of the involved lymph nodes and the presence or absence of human herpesvirus 8 (HHV-8).
  • Unicentric CD (UCD):
    • Lymph nodes from a single region are involved.
    • Systemic symptoms are not common.
  • HHV-8-associated multicentric CD (MCD):
    • Multiple lymph nodes are enlarged.
    • HHV-8 positive individuals.
    • Commonly seen in HIV or immunocompromised individuals.
  • Idiopathic MCD (iMCD):
    • Multiple lymph nodes are enlarged.
    • HHV-8 negative individuals.

Epidemiology

  • Incidence: 1.50 cases per 100,000 person-years
  • Peak incidence: 50-60 years
  • Sex ratio: 1:1
Condition Relative
incidence
Non-Hodgkin's lymphoma14.00
Hodgkin's lymphoma2.20
Castleman's disease1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Pathophysiology

Various pathological mechanisms have been proposed for Castleman's disease:

  • Viral stimulation:
    • HIV infection or immunodeficiency in HIV-negative cases enables HHV-8 to escape from host immune control.
    • It then replicates in lymph node plasmablasts and signals for the release of cytokines.
    • These cytokines (especially IL-6) cause clinical and pathologic symptoms.

  • Angiogenesis:
    • Vascular endothelial growth factor (VEGF) is produced in increased quantity in the affected cells. It allows for increased proliferation.



Clinical features

Lymphadenopathy is usually detected during screening or evaluation for another condition.
  • The median size of lymph nodes is 5.5 cm in some studies
  • Common sites include:
    • Chest (24%)
    • Neck (20%)
    • Abdomen (18%)
    • Retroperitoneum (14%)

Other features include:
  • Constitutional symptoms:
    • Fever >38°C (around 50% in unicentric and 100% in HHV-8 associated multicentric disease)
    • Night sweats
    • Weight loss
    • Fatigue
  • Hepatosplenomegaly (around 60%)
  • Fluid accumulation (around 20%):
    • Peripheral oedema
    • Pleural effusion
    • Ascites
  • Violaceous papules and eruptive cherry haemangiomata
  • Lymphocytic interstitial pneumonitis

Investigations

Several laboratory and radiological abnormalities can aid in the diagnosis, but the definitive diagnosis is made on biopsy. The most common histopathological variant is hyaline vascular subtype. It is seen in over 50 percent of the individuals.

Laboratory abnormalities can include:
  • Elevated inflammatory markers:
    • C-reactive protein (CRP)
    • Erythrocyte sedimentation rate (ESR)
  • Haematological abnormalities:
    • Anemia
    • Thrombocytopenia or thrombocytosis
  • Hypoalbuminemia

Radiological investigations include:
  • CT scan or MRI
    • Solitary, noninvasive mass in 50% of cases of UCD
    • Bilateral hilar and mediastinal lymphadenopathy and centrilobular nodular opacities in MCD
  • PET scan
    • Increased uptake is correlated with disease multicentricity and clinical manifestation.

Differential diagnosis

The differential diagnosis of Castleman's disease should include:
  • HIV lymphadenitis:
    • Generalized lymphadenopathy is more common than solitary adenopathy in HIV.
    • There is usually a history of unsafe sexual behavior, or intravenous drug abuse.
    • Serology can confirm HIV infection.

  • Lymphoma:
    • Lymphomas can present with diffuse or solitary lymphadenopathy.
    • B symptoms such as night sweats, fever, weakness, malaise, etc may or may not be present.
    • Biopsy and immunohistochemistry are used to differentiate these conditions.

  • Follicular hyperplasia:
    • It presents with generalised lymphadenopathy that can be differentiated from Castleman's disease with the help of biopsy.

Management

Management of Castleman's disease depends on the type of disease:
  • Unicentric Castleman's disease (UCD):
    • Surgical removal of the enlarged lymph node is usually curative and is considered the gold standard for treatment.
    • Sometimes, it is not possible to remove the mass completely, eg mediastinal mass close to major vessels or main stem bronchus. In these patients, systemic therapy with immunomodulators like rituximab or embolization to reduce the size is done prior to surgery.
  • HHV-8–associated MCD:
    • Rituximab is the drug of choice.
    • For patients with concomitant HIV infection and a low CD4 count and/or higher HIV load, antiretroviral therapy (ART) should be included as well.
  • HHV-8–negative MCD:
    • Siltuximab (Sylvant) is the drug of choice. It is a monoclonal antibody that binds interleukin-6 (IL-6).
    • Tocilizumab (anti–IL-6 receptor therapy) may be used if siltuximab is not available.

Complications

The prognosis of Castleman's disease is excellent, provided that complete lymph node resection was done. There is less than 4% mortality after 10-years following treatment.

Patients are at increased risk of developing:
  • Lymphomas
    • Can present with B-symptoms such as night sweats, fever, myalgias.
    • Generalised or solitary lymphadenopathy.
  • Paraneoplastic pemphigus
    • Rare, blistering lesions develop on the skin.