What is Dr. Zubair Khalid's research focus?

Dr. Zubair Khalid specializes in molecular virology, mRNA vaccine development, and computational biology, with a focus on avian pathogens like IBDV and Avian Reovirus.

Where is Dr. Zubair Khalid currently working?

Dr. Zubair Khalid is a Postdoctoral Research Associate at the University of Maryland (UMD), specifically within the Department of Animal and Avian Sciences.

Castleman Disease: Pathology, Types, and Mechanisms

Name: Castleman Disease: Pathology, Types, and Mechanisms
Creator: Dr. Zubair Khalid

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-09-20

Castleman disease is a group of rare lymphoproliferative disorders in which one or many lymph nodes enlarge because of abnormal follicular and interfollicular changes, often accompanied by excessive cytokine production. It is classified clinically as unicentric Castleman disease (UCD), involving a single anatomic site, or multicentric Castleman disease (MCD), involving multiple lymph node stations with systemic inflammation, and histologically as hyaline vascular, plasma cell, or mixed type [1][2].

Castleman disease matters because it sits at a diagnostic crossroads. It produces enlarged nodes that radiologically and clinically mimic lymphoma, tuberculosis, autoimmune disease, and soft tissue tumors, yet it is not a malignancy in the conventional sense and its treatment is completely different [3][4][5]. Getting the classification right determines whether a patient needs one operation or years of immunotherapy. This article walks through the pathology, the three histologic patterns, the cytokine and viral mechanisms, and the diagnostic pitfalls that trip up students and clinicians alike.

What Castleman Disease Actually Is

Castleman disease, also called angiofollicular lymph node hyperplasia or giant lymph node hyperplasia, is a heterogeneous benign lymphoproliferative disorder [1][2]. The older names describe the microscopic appearance: enlarged lymphoid follicles wrapped in vascular tissue, forming a mass that is often hypervascular on imaging [2][6].

The term covers several entities with different causes and prognoses. The clinical split is UCD versus MCD. UCD is a localized process, usually confined to one lymph node region, and often without systemic symptoms [1]. MCD is generalized lymphadenopathy with aggressive systemic features that can resemble malignant lymphoma [1].

The etiologic split matters just as much. MCD divides into idiopathic MCD (iMCD), Kaposi sarcoma-associated herpesvirus/human herpesvirus-8-associated MCD (HHV-8 MCD), and POEMS-associated MCD, where POEMS stands for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes [1][7].

One point that confuses beginners: Castleman disease is not one disease with one cause. It is a shared histologic reaction pattern with several distinct upstream drivers.

Why the Diagnosis Matters in Veterinary and Comparative Pathology

In veterinary medicine, the same follicular and interfollicular reaction patterns appear in reactive lymph nodes, in feline and canine lymphomas, and in nodes draining chronic inflammatory lesions. Castleman disease as a named entity is rarely confirmed in dogs and cats, but the comparative biology is instructive for two reasons. First, it teaches the principle that a lymph node can enlarge massively through immune activation rather than through clonal malignant transformation. Second, the IL-6 and herpesvirus mechanisms described in human medicine give a template for understanding cytokine-driven lymphoproliferation generally.

For the pathology student, Castleman disease is the classic example of a lesion where diagnosis cannot rest on any single feature. Regressed germinal centers alone occur in reactive and neoplastic nodes. Sheets of plasma cells alone occur in plasmacytoma, chronic inflammation, and IgG4-related disease. The diagnosis is a synthesis of architecture, vascularity, immunophenotype, and clinical context [1][8][5].

The Three Histologic Patterns

Castleman disease has three recognized histologic subtypes: hyaline vascular (HV), plasma cell (PC), and mixed hyaline vascular and plasma cell type [1][2][9]. These describe what the pathologist sees under the microscope, not where the disease is or what causes it.

Hyaline Vascular Type

Hyaline vascular is the most common pattern in unicentric disease [10]. Its defining triad is:

Regressed (atrophic) germinal centers
Penetrating vessels that traverse the germinal center, sometimes called "lollipop" lesions
Expanded mantle zones, where small lymphocytes arrange in concentric rings described as an onion-skin appearance

The onion-skin arrangement of mantle zone lymphocytes around an atrophic, vessel-penetrated germinal center is the single most recognizable feature [3]. Hyalinized blood vessels are distributed through both follicular and interfollicular areas, and the interfollicular stroma can show wide fibrosis or actual hyalinization [11].

That combination of regressed follicles and thickened vessel walls explains the name. It also explains why HV lesions enhance brightly on arterial-phase imaging: they are genuinely vascular masses [6].

Plasma Cell Type

The plasma cell pattern is dominated by sheets of plasma cells in the interfollicular zone, with hyperplastic rather than regressed germinal centers [1][8]. Where HV disease produces atrophic follicles, PC disease produces busy, active-looking follicles surrounded by antibody-secreting cells.

Plasma cells in this pattern can show lambda light chain restriction, meaning the plasma cell population is skewed toward one light chain even though the process is not obviously malignant [8]. That finding is a genuine diagnostic trap, because light chain restriction usually raises concern for a clonal plasma cell neoplasm.

Plasma cell type is the most common pattern in multicentric disease [10]. It frequently presents with systemic inflammatory symptoms and can involve skin, producing disseminated dark brown papules, patches, and plaques [9].

Mixed Type

Mixed disease shows features of both patterns in the same node or in different nodes from the same patient [1][9]. A node may contain hyperplastic follicles with plasma cell infiltrates alongside regressed, vessel-penetrated follicles. Mixed histology is common in HHV-8-associated MCD, where lymph node biopsies show HHV-8 latency-associated nuclear antigen 1 (LANA-1) positivity in lymphoid cells together with mixed hyaline vascular and plasma cell features [7][12].

Mixed disease is also a reminder that the three categories are a convenience for communication, not a fixed biology. Individual nodes can transition between patterns over time or between sites.

Reading a Lymph Node Micrograph

When you look at a Castleman lymph node micrograph, scan it in a fixed order so you do not anchor on the first striking feature.

At low magnification, assess the overall architecture. Is the node's normal cortical and medullary organization preserved or effaced? Castleman nodes retain a follicular architecture, which is the first feature separating them from most lymphomas.

Move to the follicles. Are germinal centers present, and are they large and active or small and regressed? Look for a vessel entering the center of a follicle, the penetrating vessel of HV disease. Look at the mantle zones. Are they thin, normal, or expanded into concentric rings?

Move to the interfollicular zone. Is it packed with plasma cells, with small lymphocytes, or with a mixture? Are there hyalinized vessel walls? Is there fibrosis?

Finish with immunohistochemistry and in situ hybridization. Plasma cell markers (CD38, CD138, MUM1) quantify the plasma cell component. LANA-1 staining detects HHV-8 in the lymphoid cells of HHV-8 MCD [7][12]. Kappa and lambda light chain stains detect the lambda restriction that can occur in plasma cell type disease [8].

Unicentric Versus Multicentric Disease

The clinical classification drives everything that follows.

UCD involves a single anatomic site. It typically presents as a localized lymph node enlargement, often discovered incidentally or because of mass effect [13][6]. Mesenteric and retroperitoneal locations are described, and mesenteric UCD can mimic a gastrointestinal stromal tumor, making preoperative diagnosis difficult [13][4]. UCD is generally a benign, indolent process, and complete surgical resection is the treatment of choice [13][4][6]. In a systematic review of mesenteric UCD, the mean age at diagnosis was 35.3 years and the mean lesion size was 5.51 cm [13].

MCD involves multiple lymph node stations and produces systemic inflammation. It is further subdivided into idiopathic MCD, HHV-8-associated MCD, and POEMS-associated MCD [1]. MCD can present with fever, weight loss, splenomegaly, cytopenias, and generalized lymphadenopathy that mimics malignant lymphoma [1][10]. It requires systemic therapy rather than surgery.

A subset of iMCD presents with TAFRO syndrome, an acronym for thrombocytopenia, anasarca, fever, reticulin fibrosis or renal dysfunction, and organomegaly [14]. iMCD-TAFRO shows upregulation of angiogenesis drivers including PDGFR-beta and NOTCH3, interferon signaling proteins including STAT1 and ISG15, and fibrosis markers including COL3A1 and LOXL1, with compartmentalized pathology in which intrafollicular vessels show myofibroblast markers and interfollicular regions show TGF-beta/SMAD3-mediated signaling [14].

Summary Table

Feature	Hyaline Vascular (HV)	Plasma Cell (PC)	Mixed	Multicentric (MCD) overall
Typical clinical form	Usually UCD	More often MCD	Either	MCD by definition
Typical presentation	Single mass, often incidental	Systemic symptoms, generalized nodes	Variable	Fever, weight loss, splenomegaly, cytopenias
Germinal centers	Regressed, atrophic	Hyperplastic, active	Both patterns present	Variable by pattern
Mantle zones	Expanded, onion-skin	Normal to thin	Variable	Variable
Vessels	Penetrating, hyalinized	Less prominent	Variable	Variable
Plasma cells	Sparse	Sheets in interfollicular zone	Intermediate	Often prominent
IL-6 status	Elevated IL-6 transcripts in nodes [15]	Elevated IL-6 transcripts in nodes [15]	Elevated	Elevated, highest in HHV-8 positive cases [15]
HHV-8 status	Usually negative	Usually negative in iMCD, positive in HHV-8 MCD	Often positive in HHV-8 MCD	Positive in HHV-8 MCD, negative in iMCD
First-line treatment	Surgical resection [13][4][6]	Systemic therapy for MCD	Systemic therapy for MCD	Siltuximab or rituximab-based regimens depending on subtype [16]

The Role of IL-6

Interleukin-6 (IL-6) is a cytokine that drives acute phase responses, B cell differentiation, and plasma cell survival. It is the central mediator of the inflammatory manifestations of Castleman disease.

A key study used RNA in situ hybridization and a dual in situ hybridization/immunohistochemistry technique to quantify IL-6 expression and its spatial distribution in lymph nodes from Castleman disease patients. IL-6 expression was increased in all Castleman disease lymph nodes regardless of clinical and pathological subtype [15]. The highest levels were found in HHV-8-positive cases, and the only statistically significant difference in IL-6 expression was between HHV-8-positive MCD and the non-Castleman reactive control [15].

That finding is important for two reasons. First, it shows IL-6 is a shared downstream mediator across subtypes, which is why IL-6 blockade can help patients with different histologic patterns. Second, it shows the local lymph node microenvironment is a major source of the cytokine, not just circulating cells [15].

The mechanistic chain in HHV-8 MCD is the clearest. HHV-8 infects B cells, and the viral genome encodes a viral IL-6 homolog that drives B cell proliferation and systemic inflammation, producing a life-threatening B cell lymphoproliferative disorder [16]. This is why HHV-8 MCD is a distinct entity with its own treatment logic.

In UCD and iMCD, the driver is less clear. Several hypotheses have been proposed, including occult infection, but a computational analysis using Viral-Track on sequencing data from 22 UCD, 19 iMCD, and 86 control samples found that active viral infection is unlikely to be a pathological driver of UCD or iMCD [17]. Viral sequences were found in individual patients but were not shared across patients or were also present in non-Castleman controls [17]. That negative result is genuinely informative: it argues against a single occult virus causing these two forms.

Rationale for Siltuximab and Rituximab

Siltuximab is a monoclonal antibody that binds IL-6, preventing it from engaging its receptor. The rationale follows directly from the IL-6 data. Since IL-6 transcripts are increased in Castleman disease lymph nodes across all subtypes, and the highest levels occur in HHV-8-positive disease, blocking the cytokine targets the shared downstream mediator [15].

Rituximab is a monoclonal antibody against CD20, a B cell surface marker. Its rationale differs by subtype. In HHV-8 MCD, the disease is driven by HHV-8 infection of B cells, so depleting B cells removes the reservoir of infected cells. Treatment approaches in HHV-8 MCD center on rituximab-based regimens, with outcomes varying between HIV-positive and HIV-negative populations [16]. Emerging diagnostic tools combining flow cytometry and viral transcript detection allow rapid identification of disease flares, which matters because flare management is time-critical [16].

The practical message: siltuximab targets the cytokine, rituximab targets the cell. Which one leads depends on whether the disease is driven by IL-6 excess alone or by a B cell reservoir carrying HHV-8.

Mechanism Overview

The following flow shows how a patient with lymphadenopathy is sorted toward a Castleman disease diagnosis and then toward one of the three clinical categories.

flowchart TD
    A[Lymph node enlargement] --> B[Biopsy and histology]
    B --> C{Three patterns present}
    C --> D[Hyaline vascular]
    C --> E[Plasma cell]
    C --> F[Mixed]
    D --> G{Single site or multiple}
    E --> G
    F --> G
    G --> H[Unicentric CD]
    G --> I[Multicentric CD]
    I --> J{HHV 8 positive}
    J --> K[HHV 8 associated MCD]
    J --> L[Idiopathic MCD]
    J --> M[POEMS associated MCD]

How Castleman Disease Is Worked Up in Practice

The workup proceeds in a fixed sequence.

Excisional lymph node biopsy is the diagnostic gold standard. Immunohistochemistry is an indispensable ancillary technique to routine histopathology for definitive diagnosis of proliferative lymph node lesions [1]. A fine needle aspirate or core biopsy may suggest the diagnosis but rarely provides enough architecture to classify it.

Histologic subtyping follows the criteria above. Light chain staining detects the lambda restriction seen in plasma cell type disease [8]. LANA-1 staining detects HHV-8 in HHV-8 MCD [7][12].

Staging separates UCD from MCD. Cross-sectional imaging determines whether one site or many are involved. UCD lesions are often hyperenhancing on arterial-phase CT, a feature that can help distinguish them from nerve sheath tumors and lymphomas in the differential [6].

Laboratory workup looks for systemic inflammation. Elevated C-reactive protein and IL-6, anemia, thrombocytosis, hypoalbuminemia, and hyperglobulinemia support a multicentric inflammatory process [5].

The differential diagnosis is broad and includes lymphoma, tuberculosis, IgG4-related disease, autoimmune disease, gastrointestinal stromal tumor, and other soft tissue masses [3][4][5]. In one reported adolescent case, Castleman disease was initially treated as disseminated tuberculosis before biopsy clarified the diagnosis [3].

Clinical Relevance, Limitations and Common Mistakes

Diagnosing Castleman disease on a single histologic feature is the most common error. Regressed germinal centers appear in reactive nodes, in HIV lymphadenopathy, and in some lymphomas. Penetrating vessels appear in other vascular lesions. Sheets of plasma cells appear in plasmacytoma, chronic inflammation, and IgG4-related disease. The published literature repeatedly emphasizes immunohistochemistry as indispensable for definitive diagnosis [1][8][5].

The second common mistake is assuming a light chain restriction means malignancy. Plasma cell type Castleman disease can show lambda light chain restriction without being a plasma cell neoplasm [8].

The third mistake is assuming unicentric disease cannot transform. Malignant transformation is well known in the multicentric variant, but it has been reported in unicentric disease as well, including a case in which a parotid UCD later proved to be a B cell lymphoma [18].

Several genuine uncertainties remain. The etiology of UCD and iMCD is unknown, and sequencing-based analysis has not identified a shared active viral driver [17]. The precise cellular origin of IL-6 production is still debated, though the local lymph node microenvironment appears to be a major source [15]. The border between iMCD and autoimmune disease can be difficult to draw, since iMCD can present with elevated rheumatoid factor, IgG4-positive cells, and skin findings suggestive of allergic purpura [5]. Whether every histologic pattern maps predictably to clinical behavior is not fully settled, and mixed disease in particular spans both clinical forms [1][7][12].

This article is educational and is not a substitute for veterinary diagnosis or treatment.

Quick Review

Castleman disease is classified by distribution (UCD versus MCD) and by histology (hyaline vascular, plasma cell, mixed).
Hyaline vascular type shows regressed germinal centers, penetrating vessels, and expanded onion-skin mantle zones.
Plasma cell type shows hyperplastic follicles and interfollicular plasma cell sheets, sometimes with lambda light chain restriction.
UCD is usually a single site and surgically curable. MCD is systemic and needs systemic therapy.
IL-6 transcripts are increased in all Castleman disease lymph nodes and are highest in HHV-8-positive cases.
Siltuximab blocks IL-6. Rituximab depletes the B cell reservoir in HHV-8 MCD.
No single histologic feature is diagnostic. Architecture, immunohistochemistry, and clinical context must agree.

Frequently Asked Questions

Is Castleman disease a cancer?

No. It is a lymphoproliferative disorder, meaning lymph node tissue grows abnormally through immune and cytokine-driven processes rather than through the clonal malignant transformation that defines lymphoma. It can, however, transform into lymphoma in rare cases.

What is the difference between unicentric and multicentric Castleman disease?

Unicentric disease involves one anatomic site and is usually localized and surgically curable. Multicentric disease involves multiple lymph node stations and produces systemic inflammation, so it needs systemic therapy.

Which histologic type is most common in multicentric disease?

Plasma cell type is the most common pattern in multicentric disease, while hyaline vascular type is the most common pattern in unicentric disease.

Is Castleman disease caused by a virus?

In HHV-8-associated multicentric disease, yes. HHV-8 infects B cells and drives the cytokine storm. In unicentric disease and idiopathic multicentric disease, sequencing-based analysis has not identified a shared active viral driver.

Why is siltuximab used in Castleman disease?

Siltuximab binds IL-6, the cytokine that mediates the inflammatory symptoms. IL-6 expression is increased in Castleman disease lymph nodes across all subtypes, so blocking it targets a shared pathway.

Can Castleman disease be cured with surgery?

Unicentric Castleman disease is usually curable with complete surgical resection, and recurrence after excision is uncommon. Multicentric Castleman disease is not treated with surgery as a curative approach.