Among non-neoplastic conditions, the plasma cell variant of Castleman disease may mimic lymph nodes biopsied in the setting of rheumatoid arthritis or syphilitic (luetic) lymphadenitis due to overlapping features of follicular hyperplasia and increased interfollicular plasma cells.
In addition, lymphadenopathy associated with IgG4-related disease may show features that overlap with Castleman disease.
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The diagnosis of rheumatoid arthritis, syphilis, or IgG4-related disease can be readily established based on clinical and laboratory features. In addition, Castleman disease lacks the histiocytic inflammation and inflamed vasculature seen in syphilis in which spirochetes can be identified using special histochemical stains or antitreponemal immunohistochemistry.17,20-22
Perhaps the most challenging histological distinction in the pathological diagnosis of MCD is with that of HIV-related generalized lymphadenopathy, which is characterized by plasmacytosis, vascular prominence, and hyperplastic or regressive changes in the follicles of involved lymph nodes depending on their stage of evolution.
However, HIV-related lymphadenopathy should not contain plasmablasts positive for HHV-8 that characterize HIV-associated MCD. For the diagnosis of other subtypes of Castleman disease in the setting of HIV infection, one should adhere to strict morphological criteria given the known histological overlap between these entities.17
Staging
Once Castleman disease is confirmed and the histological subtype has been identified, clinical staging guides treatment decisions and prognosis. The goals of the staging and pretreatment evaluation in Castleman disease are to (1) determine whether the patient has unicentric or multicentric disease, (2) identify patients with systemic inflammatory manifestations of Castleman disease, and (3) assess for the presence of HIV, as well as associated conditions and malignancies.
The initial laboratory evaluation of patients with Castleman disease includes a complete blood count, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), complete metabolic panel, and albumin. HIV testing should be performed in all patients.
Plasma HHV-8 DNA levels should be obtained, because these levels correlate with symptomatic disease and may serve as a helpful biomarker, both to support the diagnosis of MCD and to monitor disease activity and response to therapy.
Although levels of cytokines, most notably IL-6 and IL-10, are important in the pathogenesis of Castleman disease and have been used as surrogate markers of disease activity in clinical studies, we do not recommend routinely measuring them. Serum protein electrophoresis with immunofixation should be obtained when POEMS syndrome is suspected.
In patients with HIV-associated MCD, a thorough skin examination should be performed to assess for previously undiagnosed Kaposi sarcoma given the common concurrent presentation of these entities.
Computed tomography of the chest, abdomen, and pelvis should be obtained at the time of diagnosis to assess for adenopathy and splenomegaly. This imaging modality also helps inform the question of resectability in patients with UCD.
A role for routine positron emission tomography has not been established in the setting of Castleman disease, although involved nodes in MCD are quite fludeoxyglucose-avid.
Unicentric Castleman Disease
Epidemiology
UCD most commonly presents in the third and fourth decade of life, with the mean age of diagnosis being 34 years (range, 2–84 years); UCD also has a slight female predominance (1.4:1).23 No association with HIV or HHV-8 infection exists and epidemiological risk factors have not been established.
Clinical Presentation
UCD may be asymptomatic at diagnosis and be incidentally discovered on chest or abdominal imaging performed for other reasons. Other patients may present with painless lymphadenopathy or local anatomical symptoms varying by location. Common sites of presentation in UCD include the chest (30%), neck (23%), abdomen (20%), retroperitoneum (17%), and, rarely, the axilla (5%), groin (3%), or pelvis (2%).23
Intrathoracic disease is frequently found along the tracheobronchial tree or lung hila. Thoracic disease may present with cough, hemoptysis, dyspnea, or chest discomfort. Abdominal, retroperitoneal, and pelvic disease may present with abdominal or back discomfort.2 Bowel and ureteral obstruction have been described as presenting symptoms, but they are rare.24
Disease confined to the peripheral lymph node chains, including the neck, axilla, or groin, may present with nontender lymphadenopathy. Systemic manifestations, including B symptoms (fevers, drenching night sweats, and weight loss) and laboratory abnormalities (anemia, elevated inflammatory markers, hypergammaglobulinemia, and hypoalbuminemia) are uncommon in unicentric disease, but such symptoms are observed frequently among patients with the plasma cell variant.
Management
The optimal therapy for UCD is surgical resection, which is usually curative if the disease is amenable to complete resection.3,23 For disease that cannot be completely excised, radiation therapy is an option due to its high rates of objective response, including complete responses in nearly one-half of reported cases.25-31
For select patients who are not candidates for surgical excision, but who are also not candidates for radiation therapy based on the location of the disease, partial resection followed by clinical observation alone may result in lengthy remissions; however, such treatment warrants careful attention to local progression.
Select patients who are asymptomatic with a low disease burden who cannot be treated with either surgery or radiation may be closely followed, given the often indolent nature of the disease. Systemic options for MCD, as necessary, should be considered for patients with symptomatic local disease who cannot be treated with surgery or radiation or for those whose disease fails to respond to such treatment.
