I. What every physician needs to know.

Castleman’s disease, also known as angiofollicular hyperplasia, is a rare and benign disorder of lymph node proliferation coined by the American pathologist Benjamin Castleman in 1965.

Specifically, it is defined as a follicular hyperplasia of lymph nodes with abnormally increased vascularity. It can be classified as unicentric or multicentric based on radiological findings and histologically as hyaline vascular, plasmacytic or of a mixed cellular variety. Human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8) status are also important in its classification and assessment as they are often positive in those affected with multicentric disease.

II. Diagnostic Confirmation: Are you sure your patient has Castleman's disease?

The diagnosis of Castleman’s disease requires lymph node biopsy with histological analysis and immunohistochemical staining. Analysis will show polyclonal angiofollicular lymphoid hyperplasia. The unicentric form most often shows the hyalinovascular type, while the multicentric type most often shows the plasmacytic or mixed cellular variety. It remains a diagnosis of exclusion as several diseases can also mimic this histopathology.

A. History Part I: Pattern Recognition:

The localised form often presents asymptomatically and may be found on routine exam or imaging. Sites that are preferably involved in decreasing order are the abdomen, superficial lymph nodes and the mediastinum, hence palpating an abdominal mass may be a method of discovery. By history, one third of these patients may show malaise, weakness, fever, and weight loss.

The multicentric form usually does present symptomatically with more than half of patients presenting with weight loss and fever. Most do exhibit peripheral lymphadenopathy, as well as hepatomegaly, splenomegaly and skin changes characteristic of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes). Associated infections include HIV and HHV-8, with HHV-8 thought to be involved in the pathophysiology of the disease in HIV infected patients.

B. History Part 2: Prevalence:

The prevalence of the disease is unknown, but it has been estimated at less than 1 in 100,000. It can occur at any age. The localised form is the most frequent (more than 400 cases reported), while the multicentric form is less frequent and often occurs in association with HIV infection.

C. History Part 3: Competing diagnoses that can mimic Castleman's disease.

Rheumatoid arthritis, Sjögren’s syndrome, congenital immune deficiencies, reactions to cancers, and hemopathies or vaccinations, syphilis, manifestations of membranous glomerulonephritis, and some cutaneous diseases may mimic the disease with lymph node hyperplasia of the angiofollicular type.

D. Physical Examination Findings.

Lymphadenopathy is the hallmark exam finding of the disease and peripheral lymphadenopathy is observed in 81% of cases. Other associated physical exam findings include hepatosplenomegaly.

POEMS syndrome is observed in approximately 23% of cases and can show skin hyperpigmentation, skin thickening, sclerodermoid changes, and hypertrichosis. Other skin changes, including whitening of the proximal nails (Terry nails), peripheral edema, hyperhidrosis, clubbing of the fingers, Raynaud’s phenomenon, and angiomas can also be observed.

Castleman’s disease can be associated with Kaposi’s sarcoma and its characteristic papular nodules that may be red, purple, brown, or black and found on the skin, in the gastrointestinal or respiratory tracts. Finally, Castleman’s may sometimes present with systemic amyloidosis with nephrotic syndrome and present with its characteristic physical exam findings, such as edema and waxy, translucent skin lesions, particularly around the facial and oral areas.

E. What diagnostic tests should be performed?

The hallmark diagnostic test is lymph node biopsy, with the gold standard being full lymph node excision. Analysis will show polyclonal angiofollicular lymphoid hyperplasia. Amyloid can also be found within lymph tissue of those affected.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In multicentric disease, a HIV antibody should be performed, as there is a high association of HIV infected patients with its multicentric form. An interleukin 6 (IL-6) level may be elevated in systemic disease as well.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Computed tomography (CT) scans and magnetic resonance imaging (MRI) can be used to identify lymphadenopathy if needed and rule out other signs of infection or malignancy. Positron emission tomography (PET) scanning can also be used in diagnosis as Castleman’s lymphadenopathy will show less metabolic activity before treatment than other malignant diseases, such as lymphoma.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A

III. Default Management.

The mainstay of management remains staging with diffuse imaging (CT or PET) and appropriate biopsy to ascertain whether the disease is present in its localised or multicentric form. The localized form may be treated with surgical excision, while the multicentric form requires systemic therapy.

A. Immediate management.

Initial management involves physical exam assessment and basic laboratories including a complete blood count and basic electrolyte panel, particularly looking for anemia, renal failure or signs of infection, with the goal of stabilization.

Once stabilization is obtained, surgical excision is the preferred treatment in most cases of unicentric Castleman’s disease and adjuvant therapy with steroids and/or Rituxan before surgery can be very useful to shrink bulky or inoperable disease. In some cases, radiotherapy has proven effective, although this is currently usually avoided.

A number of therapies have been used for multicentric disease including intravenous immunoglobulin, anti-herpes drugs such acyclovir and Valganciclovir (particularly in HIV and HHV-8 positive populations), combination chemotherapy (e.g. CHOP – cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone), thalidomide, and anti-IL-6 therapy, with limited success and in intractable cases even autologous stem cell transplantation has been attempted. Surgery may also be useful in debulking the disease.

B. Physical Examination Tips to Guide Management.

Normal palpation for lymphadenopathy can be used to monitor treatment. For patients treated with chemotherapy and relapsed multicentric disease, monitoring for signs of infection, rashes and mucositis will be imperative during treatment.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There remain no definitive guidelines for management of the disease, however increased IL-6 production is associated with the disease, and some authors describe falling levels of systemic IL-6 with successful treatment. HHV-8 viral loads may also fall in those who are infected and being successfully treated for multicentric disease. Anemia and renal failure, which may be complications of the disease, may also be monitored with basic laboratories.

D. Long-term management.

There are no guidelines for long-term management of multicentric disease. Patients may undergo various therapies with chemotherapy regimens, steroids or possibly a chimeric monoclonal antibody until disease progression and/or infection limits further treatment.