Hospital Medicine

Castleman's disease (angiofollicular hyperplasia)

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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.

E. Common Pitfalls and Side-Effects of Management

N/A

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Infection may be the primary risk in Castleman's patients. Relapsed forms of multicentric disease will often progress to lymphoma and/or become more susceptible to infection because of progression. Those with multicentric disease are often treated with systemic chemotherapy or steroids, and should be treated as immunosuppressed and susceptible to infection with typical and atypical organisms.

B. Anticipated Length of Stay.

N/A

C. When is the Patient Ready for Discharge.

For the localised form with patients who undergo surgery, the patient may be discharged when appropriately stable from surgery. The patient with multicentric disease may be undergoing chemotherapy, and may be discharged when therapy is completed and the patient is appropriately stable, i.e. a neutropenic patient without infection or with appropriately treated infection.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Follow-up should be arranged with a specialist in hematological malignancies and arranged within 1-2 weeks of discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

  • A basic electrolyte panel with the addition of albumin, total protein and a fasting lipid panel, as the disease has sometimes been associated with nephrotic syndrome

  • A complete blood count in those receiving chemotherapy and because the disease can be associated with a microcytic anemia

  • For disease progression of multicentric disease, some clinicians follow an IL-6 level and/or a HHV-8 viral load

E. Placement Considerations.

Those with multicentric disease often have a poor prognosis with a median survival time of less than 3 years. After several relapses, hospice stay may be appropriate for certain populations.

F. Prognosis and Patient Counseling.

In the unicentric form of the disease, surgical resection is often curative, and the prognosis is excellent. Full recovery may be achieved in nearly 90% of cases.

The long-term prognosis of systemic Castleman's disease is poor. The disease tends to persist for years and in some cases, may be associated with simultaneous or subsequent lymphomas, plasmacytomas and vascular neoplasms including Kaposi's sarcoma.

Hodgkin's disease may be accompanied or preceded by lymph node changes that greatly resemble those of Castleman's disease of either type. Remission may be obtained with systemic therapy, but relapse is common and overall median survival may be 30 months. Death may usually come from infection or complications of malignant transformation.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients undergoing chemotherapy may need to be discharged on prophylactic antibiotics, such as a fluoroquinolone, depending on their treatment type, in anticipation of neutropenia and infection risk.

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