Castleman disease

Castleman disease,also known as angiofollicular lymph node hyperplasia or giant lymph node hyperplasia, is an uncommon benign B-cell lymphoproliferative condition. It can affect several regions of the body although commonly described as a solitary mediastinal mass.

There are two distinct subtypes of Castleman disease:

• unicentric Castleman disease:
  • more common
  • localised, localised,  and locally treated
  • associated with minimal symptoms, and locally treated
• multicentric Castleman disease:
  • usually in the context of HIV infection, being a
  • systemic disease characterised by diffuse lymphadenopathy, anemia, splenomegaly, and systemic inflammatory symptoms

Epidemiology

Unicentric Castleman disease typically occurs in children and young adults (3^rd and 4^th decades), with a slight female predominance (1.4:1) ¹⁵.

Multicentric Castleman disease, on the other hand, occurs in an older population (5^th and 6^th decades), with a slight male predominance ¹⁵. HIV is a relevant risk factor for this condition, and it has been demonstrated that all the HIV patients with multicentric Castleman disease are coinfected with the human herpesvirus 8 (HHV-8).

Clinical presentation

Unicentric Castleman disease is usually asymptomatic and incidentally found on routine exams for other reasons. Depending on the anatomical site, a painless lymphadenopathy may be noted.

Multicentric Castleman disease has an exuberant clinical presentation due the systemic inflammation, with symptoms such as fevers, night sweats, fatigue, and weight loss, and clinical signs of generalised lymphadenopathy, hepatosplenomegaly, and fluid retention.

Haematological abnormalities such as anaemia, elevated inflammatory markers, hypergammaglobulinemia, and hypoalbuminaemia are commonly found in patients with multicentric Castleman disease ¹⁵.

Pathology

The disease is of unknown aetiology, but the most widely accepted theory is that Castleman disease is a chronic low-grade inflammatory process. The interleukin 6 in unicentric Castleman disease and both interleukin-6 and HHV-8 in multicentric Castleman disease were demonstrated to play a critical role in pathogenesis and symptomatology of the disease ¹⁵.

The disease is characterised by hypervascular lymphoid hyperplasia. There are also several recognised subtypes based on histopathology ^1-2:

• hyaline vascular
  • most common ~90%, corresponding to most cases of the unicentric Castleman disease
  • most commonly found in the mediastinum
  • classically appears as an avidly enhancing mediastinal mass at CT and MRI
  • increased numbers of small hyalinised blood vessels within and between the lymphoid follicles, which show obliteration of the medullary sinuses
  • “onion-skinning” arrangement of the small lymphocytes of the mantle zones, forming concentric rings around the germinal center
• plasma cell
  • often multicentric
  • hyperplastic follicles of varying sizes, which show patent medullary sinuses
  • less enhancing
  • may be more symptomatic ⁵
• HHV-8–associated Castleman disease⁸
• multicentric Castleman disease not otherwise specified

Castleman disease is an exclusion diagnosis usually made by excisional biopsy of an affected lymph node. Alternatively, core needle biopsy can be performed when the excision is not possible ¹⁵.

Location

The distribution is as follows:

• thorax: ~70%
• abdomen/pelvis and retroperitoneum: 10-15%
• neck: 10-15%

Multicentric Castleman disease may involve all of the above, and is associated with a more complex clinical course with systemic symptoms including fever and organomegaly.

Associations

• POEMS syndrome
• osteosclerotic myeloma
• Kaposi sarcoma
• AIDS: especially multicentric ⁹
• amyloidosis ¹⁰
• chordoid meningioma ¹⁶

Radiographic features

Plain radiograph

Thoracic lesions may present as mediastinal masses.

Additional findings include ¹⁹:

• displacement of adjacent structures due to mass effect
• ipsilateral pleural effusion
• periosteal reaction

Ultrasound

Both hyaline-vascular and plasma cell types present as hypoechoic masses and nodules ¹⁷. The ultrasonographic findings are not specific and can be indistinguishable from lymphoma and other lymphadenopathy. Doppler examination of hyaline-vascular type may reveal exuberant vascularity with predominantly peripheral flow, prominent penetrating feeding vessels entering the hilum, and low-resistance arterial wave pattern ¹⁸.

CT

For mediastinal lesions: CT chest

• commonly seen as a solitary mediastinal mass, infiltrative mass, multiple lymph nodes or rarely as matted lymphadenopathy (with or without a dominant mass) in a single mediastinal compartment
• typical arborising calcification may be seen within the mass in 15% of cases
• hyalin vascular type typically shows intense homogeneous enhancement following contrast
• dynamic CT demonstrates early rapid enhancement with washout in the delayed phase
• plasma cell type are multicentric and are less enhancing ⁸

For abdominal lesions: CT abdomen

• most commonly, a single well-defined abdominal mass
• location is variable, and includes retroperitoneum, mesentery and porta hepatis ³
• enhancement is homogeneous, or in larger lesions (>5 cm) may demonstrate central hypoattenuation consistent with necrosis.
• variable pattern of calcification, including arborising calcification.

For multicentric disease: multi-region CT

• bilateral hilar and mediastinal lymphadenopathy
• centrilobular nodules
• diffuse abdominal lymphadenopathy
• hepatosplenomegaly
• ascites

MRI

General signal characteristics include:

• T1: iso to hyperintense relative to skeletal muscle
• T1 C+ (Gd): shows enhancement
• T2: arborising calcification may be seen as low signal
• low values on ADC may be encountered ^13-14

FDG-PET(/CT)

There is growing evidence that active Castleman disease is FDG avid, why ¹⁸F-FDG PET(/CT) is more sensitive than CT alone and may be an effective diagnostic tool, especially if performed with hybrid imaging part SOA contrast-enhanced CT ¹². Discrimination between uni- and multicentric disease, mapping of the extent of disease and monitoring disease progression seems possible, especially if confirmed in larger series ^7,12.

Treatment and prognosis

For unicentric Castleman disease treatment is surgical, with good prognosis (can be curative).

Multicentric Castleman disease may be treated with any combination of surgery, chemotherapy and prednisolone ⁶.  Available treatments include also antiviral strategies (targeting HHV-8), and monoclonal antibody therapies targeting CD20 or IL-6 ^15. Prognosis is relatively poorer.

Patients with multicentric Castleman disease and POEMS syndrome are usually treated with high-dose immunosuppressive agents and steroids. If immunosuppression fails, autologous peripheral blood stem cell transplantation is recommended ¹⁹. 

History and etymology

The condition was first published by Benjamin Castleman in 1954 ⁴.

Differential diagnosis

For thoracic lesions consider:

• if anterosuperior, consider: differential for an anterosuperior mediastinal mass
• if posterior, consider: differential for a posterior mediastinal mass