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Mimickers and associated neoplasms of Castleman disease

Mimickers and associated neoplasms of Castleman disease
2025-04-11
(Press-News.org)

Castleman disease (CD) is a rare, non-clonal lymphoproliferative disorder that manifests with a wide range of histologic and clinical features. It is classified clinically into unicentric (UCD) and multicentric (MCD) forms and histopathologically into hyaline vascular (HV-CD), plasma cell (PC-CD), and mixed types. UCD typically presents as an isolated lymph node enlargement, often asymptomatic, whereas MCD involves multiple nodal sites and systemic symptoms. MCD may be associated with human herpesvirus 8 (HHV8), idiopathic origins (iMCD), POEMS syndrome, or TAFRO syndrome. Given its overlap with various reactive and neoplastic diseases, CD is diagnostically challenging and often mimicked by other conditions.

Histopathologic Features

HV-CD is marked by regressed germinal centers, concentric mantle zones ("onion-skinning"), and prominent sclerotic blood vessels, forming a "lollipop" appearance. The interfollicular regions show vascular proliferation and clusters of plasmacytoid dendritic cells.

PC-CD is characterized by interfollicular sheets of plasma cells and less prominent vascular changes. A third of these cases may show monotypic plasma cells, and overlap with HV features may be present.

Cytogenetics and Molecular Findings
Clonal cytogenetic abnormalities suggest a possible neoplastic origin in HV-CD, involving follicular dendritic cells. Key mutations in UCD include PDGFRB N666S, while iMCD is associated with mutations in NCOA4, SETD1A, and DNMT3A, among others. Dysregulation of genes involved in immune response, angiogenesis (e.g., CXCL13), and oxidative phosphorylation is noted, highlighting diverse molecular landscapes.

Diagnostic Criteria
Diagnosis relies on a combination of clinical, laboratory, and histological findings. HV-CD is defined by vascularized regressed follicles and fibrotic stroma. PC-CD diagnosis requires interfollicular plasmacytosis, polytypic or occasionally monotypic plasma cells, and exclusion of other conditions such as infections or autoimmune disease.

Mimickers of Castleman Disease
Numerous benign and malignant conditions can simulate CD:

・ Lymphomas: Follicular hyperplasia, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma may resemble HV-CD. Angioimmunoblastic T-cell lymphoma (AITL) can mimic HV-CD due to similar vascular and plasmacytic features.

・ Classic Hodgkin Lymphoma (CHL): Particularly the interfollicular variant of CHL may overlap with PC-CD, making identification of Reed-Sternberg cells essential.

・ Follicular Dendritic Cell (FDC) Sarcoma: HV-CD often shows FDC proliferation, which can evolve into FDC sarcoma.

・ Plasma Cell Neoplasms: These can appear similar to PC-CD, especially when monotypic plasma cell populations are present.

・ IgG4-related Disease (IgG4-RD): Frequently overlaps with PC-CD and iMCD; differentiation requires histology, IgG4+/IgG+ plasma cell ratio, and clinical correlation.

・ Autoimmune Conditions: Rheumatoid arthritis, lupus, Still’s disease, and autoimmune lymphoproliferative syndrome (ALPS) can present with Castleman-like lymphadenopathy.

・ Infectious Causes: EBV, HHV8, HIV, CMV, and tuberculosis may cause lymph node changes similar to CD.

Associated Neoplasms
CD is linked to an increased risk of both hematologic and non-hematologic malignancies:

・ Plasma Cell Neoplasms: Especially within POEMS syndrome, characterized by polyneuropathy and monoclonal gammopathy.

・ Lymphomas: CD is associated with classic Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and peripheral T-cell lymphoma. These associations are often IL-6 driven.

・ Kaposi Sarcoma: Commonly seen in HHV8-positive MCD, often with concurrent HIV infection.

・ FDC Sarcoma: Can arise from HV-CD, supporting a neoplastic continuum from CD to malignancy.

・ Indolent T/B-Lymphoblastic Proliferation: Seen in CD with clusters of immature lymphoblasts that lack atypia and clonality, requiring careful immunohistochemical differentiation from leukemia/lymphoma.

Conclusions
Castleman disease encompasses a spectrum of histologic and clinical presentations, often overlapping with mimicking conditions. Accurate diagnosis requires a multidisciplinary approach integrating histopathology, molecular diagnostics, and clinical context. Recognizing mimickers and understanding associated neoplasms are essential for correct classification and management. Future studies focused on molecular pathogenesis may help refine the diagnosis and therapeutic strategies for CD and its related disorders.

 

Full text

https://www.xiahepublishing.com/2771-165X/JCTP-2024-00047

 

The study was recently published in the Journal of Clinical and Translational Pathology.

Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.

 

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[Press-News.org] Mimickers and associated neoplasms of Castleman disease