Castleman disease is defined by a range of characteristic features seen on microscopic analysis (histology) of tissue from enlarged lymph nodes. Variations in the lymph node tissues of patients with CD have led to 4 histological classifications:
• Plasmacytic: increased number of follicles with large hyperplastic germinal centers and sheetlike plasmacytosis (increased number plasma cells). Germinal centers may also show regressed features
• Hyaline vascular: regressed germinal centers, follicular dendritic cell prominence or dysplasia, hypervascularity in interfollicular regions, sclerotic vessels, prominent mantle zones with an "onion-skin" appearance.
• Hypervascular: similar to hyaline vascular features, but seen in iMCD rather than UCD. Includes regressed germinal centers, follicular dendritic cell prominence, hypervascularity in interfollicular regions, and prominent mantle zones with an "onion-skin" appearance.
• Mixed: presence of a combination of hyaline vascular/hypervascular and plasmacytic features in the same lymph node.
UCD most commonly demonstrates hyaline vascular features, but plasmacytic features or a mix of features may also be seen. iMCD more commonly demonstrates plasmacytic features, but hypervascular features or a mix of features are also seen. All cases of HHV-8-associated MCD are thought to demonstrate plasmablastic features—similar to plasmacytic features, but with plasmablasts present. The clinical utility of subtyping Castleman disease by histologic features is uncertain, as histologic subtypes do not consistently predict disease severity or treatment response. Guidelines recommend against using histologic subtype to guide treatment decisions. Staining with latency-associated nuclear antigen (LANA-1), a marker for HHV-8 infection, should be measured in all forms of Castleman disease but is positive only in HHV-8-associated MCD.

Diseases other than Castleman disease can present with similar histologic findings in lymph node tissue, including:
• Infectious causes: Epstein-Barr virus, human immunodeficiency virus, tuberculosis
• Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis
• Lymphoproliferative disorders: lymphoma, autoimmune lymphoproliferative syndrome

Unicentric Castleman disease was first described in a case series by Benjamin Castleman in 1956. By 1984, a number of case reports had been published describing a multicentric variant of the disease and with some reports describing an association with Kaposi's sarcoma. In 1995, the association between HHV-8 and Castleman disease was described in patients with HIV. Formal diagnostic criteria and definition of the disease was established in 2016, which will allow for better understanding and the ability to appropriately track and research CD. In 2017, international consensus diagnostic criteria for idiopathic multicentric Castleman disease (iMCD) were established for the first time. In 2018, the first treatment guidelines for iMCD were established. In 2020 the first evidence based diagnostic criteria and treatment guidelines were established for unicentric Castleman disease.

World Castleman Disease Day was established in 2018 and is held every year on July 23. This date was chosen for Benjamin Castleman's initial case series describing Castleman disease, which was published in July 1956, and the diagnostic criteria for idiopathic multicentric Castleman disease, which were published in the journal Blood on March 23, 2017.

The Castleman Disease Collaborative Network (CDCN), founded in 2012, is the largest organization dedicated to Castleman disease. It is a global initiative dedicated to research and treatment for Castleman disease (CD) and to improve survival for all patients with CD. The CDCN works to achieve this by facilitating collaboration among the global research community, mobilizing resources, strategically investing in high-impact research, and supporting patients and people supporting them.