Castleman Disease Workup

The workup for Castleman disease (CD) varies among the subtypes.

Patients with unicentric CD (UCD) may have elevated inflammatory markers such as C-reactive protein (CRP). The diagnosis is made by histologic examination of an excised lymph node. Imaging should be performed to confirm that involvement is unicentric (ie, limited to a single lymph node or single region of enlarged lymph nodes) and to select the best lymph node for surgical excision.

Histopathologically, the lymph nodes demonstrate a constellation of "CD-like" features along a spectrum, including small or large germinal centers, follicular dendritic cell (FDC) prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. Lymph node features of the different histopathological subtypes of UCD are as follows:

• Hyaline vascular –  Atrophic germinal centers, onion-skinning mantle zones, hypervascularization, and FDC prominence ^[8]
• Plasma cell – Hyperplastic germinal centers as well as occasional atrophic germinal centers and interfollicular plasmacytosis
• Mixed – Lymph nodes demonstrate features of both the hyaline vascular and plasma cell subtypes

In human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (MCD), laboratory studies show elevation of inflammatory markers such as CRP, and evidence of organ dysfunction. The diagnosis is made by histologic examination of an excised lymph node. Imaging should be performed to confirm that the patient has multiple regions of enlarged lymph nodes (ie, multicentric involvement) and to select the best lymph node for surgical excision. 

Histopathologically, the lymph nodes in HHV-8–associated MCD demonstrate a contellation of "CD-like" features, including small or large germinal centers, hypervascularity, lambda-restricted polyclonal plasmacytosis, increased plasmablasts, and/or expansion of polyclonal B cells and T cells. IgH gene rearrangement studies should be performed on the lymph node specimen to rule out a clonal disorder (eg, occult lymphoma). Latency-associated nuclear antigen–1 (LANA-1) staining for HHV-8 by immunohistochemistry should be performed on all cases to confirm that HHV-8 is the pathological driver.

HHV-8–negative/idiopathic MCD (iMCD) also features elevated inflammatory markers such as CRP, and organ dysfunction. In 2017, an international panel published diagnostic criteria for iMCD. ^[10] For diagnosis, patients must meet both major criteria (characteristic lymph node histopathology and multicentric lymphadenopathy) and at least 2 of the 11 minor criteria, including at least 1 laboratory abnormality. Imaging should be performed to confirm that there are multiple regions of enlarged lymph nodes (multicentric) and to select the best lymph node for surgical excision. Histopathologically, the lymph nodes demonstrate a contellation of "CD-like" features along a spectrum, including small or large germinal centers, FDC prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. IgH gene rearrangement studies should be performed on the lymph node specimen to rule out a clonal disorder (eg, occult lymphoma).

LANA-1 staining for HHV-8 by IHC should be performed on all cases and should be negative, confirming that HHV-8 is NOT the pathological driver. In addition, diagnosis requires exclusion of infectious, malignant, and autoimmune disorders that can mimic idiopathic MCD (see DDx).

The clinical minor diagnostic criteria comprise the following:

• Constitutional symptoms
• Hepatosplenomegaly
• Anasarca, edema or effusions
• Eruptive cherry hemangiomatosis or violaceous papules
• Lymphocytic interstitial pneumonitis (LIP)

The laboratory minor criteria comprise the following:

• Elevated CRP and/or ESR level
• Anemia
• Thrombocytopenia or thrombocytosis
• Hypoalbuminemia
• Kidney dysfunction
• Polyclonal hypergammaglobulinemia

Imaging is primarily helpful in determining whether the patient has UCD or a form of MCD and in assessing response to therapy.

Whole-body imaging should be performed on all patients with suspected UCD or a form of MCD.

In UCD, a single persistently enlarged lymph node associated with moderate to intense post-contrast enhancement is often found on computed tomography (CT). In such cases, Fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered to establish that the disease is limited to a single site with a relatively lower standardized uptake value (SUV) in other nodes.

In HHV-8-associated MCD and HHV-8–negative MCD, multiple enlarged mediastinal and hilar lymph nodes (1 to 3 cm diameter) may be found along with peripheral lymphadenopathy. HHV-8-associated MCD and HHV-8-negative MCD are both PET avid usually with a relatively low standardized uptake value (SUV) of 2.5-5. ^[16] Imaging cannot be used to differentiate HHV-8-associated MCD from HHV-8-negative MCD.

In patients with HHV-8–associated MCD and HHV-8–negative MCD, a chest radiograph may show one or more of the following:

• Bilateral reticular or ground-glass opacities
• Mediastinal widening
• Bilateral pleural effusions

Lung parenchymal findings may be seen on CT, including subpleural nodules, interlobular septal thickening, peribronchovascular thickening, ground-glass opacities, and patchy rounded areas of consolidation. Small to moderate bilateral pleural effusions may also be present. CT scanning of the neck, abdomen, and pelvis, with and without contrast, may also be helpful.

Imaging may be used to determine the efficacy of therapy—in UCD, to assess whether resection was complete and no residual disease exists, and in MCD (HHV-8–associated or HHV-8-negative) to assess whether multicentric lymphadenopathy has improved after medical therapy.

Laboratory findings are quite variable across the subtypes of CD (UCD, HHV-8-associated MCD, HHV-8-negative/idiopathic iMCD) and even within the three clinical subtypes of HHV-8–negative/idiopathic iMCD (POEMS associated iMCD, TAFRO syndrome iMCD, iMCD-NOS). Characteristic findings include the following:

• Complete blood cell (CBC) count – Anemia (usually mild to moderate, occasionally, the hemoglobin level is < 8 g/dL), thrombocytosis or thrombocytopenia
• Liver function tests (LFT) – Hypoalbuminemia and elevated alkaline phosphatase
• Serum protein electrophoresis, with immunofixation and quantitative immunoglobulins – Polyclonal hypergammaglobulinemia
• C-Reactive Protein (CRP) - Usually elevated
• Erythrocyte sedimentation rate (ESR) – Usually elevated
• Fibrinogen – Usually elevated
• Creatinine and blood urea nitrogen – Usually elevated
• Serologies for hepatitis B, human herpesvius–8 (HHV-8), and HIV; with quantitative assays if initial results are positive
• Interleukin-6 (IL-6) and lactate dehydrogenase (LDH) – Usually elevated
• Vascular endothelial growth factor (VEGF) – May be elevated
• Autoantibodies, such as antinuclear antibody (ANA) – May be elevated

Excisional lymph node biopsy is the preferred method of lymph node biopsy and is used to establish diagnosis. ^[15]  The other methods of lymph node biopsy are not recommended. Fine needle aspiration is not typically suitable for initial diagnosis. Core needle biopsy has limited accuracy.