Welcome to the CD Pathology Toolkit!
Here you will learn from top international experts about how they make a Castleman disease diagnosis based on histopathology. This program is not intended to be a complete diagnostic guide to Castleman disease, but rather a source that may help identify potential cases of this rare and sometimes fatal disease.
1. DISEASE OVERVIEW
Toolkit Modules:
- Disease Overview
- Pathology of Castleman Disease
- Clinical Manifestations
- Important Differential Diagnoses
- Case Studies
Castleman disease (CD) is a lymphoproliferative disorder which displays a great variation in presenting symptoms and signs. In some cases, it may result in serious complications which can lead to death.
CD is clinically manifested as either Unicentric or Multicentric.
Unicentric CD, or UCD, is localized to one lymph node station, although occasionally small, regional, satellite nodes maybe present. It generally is seen in an adult population, with the median age in the fourth decade. It is typically a symptomatic, and is curable by surgery in 95% of patients.
Multicentric CD, or MCD, is widespread, aggressive, has high morbidity and is associated with an adult population in the fifth to sixth decade.
Variations in the lymph node tissues of patients with CD have led to 4 histological classifications:
- Hyaline vascular variant
- Plasma cell variant
- Mixed cell variant
- Plasmablastic variant
Most cases of UCD are of the hyaline vascular variant. The plasma cell variant is most often found in MCD.
MCD can further be categorized into:
- HHV-8-positive/HHV-8-associated
- Idiopathic
These 2 MCD categories are distinct and prognosis differs.
CD is a rare and incompletely understood disease. While most cases tend to be managed in a community setting, there has been an increased tendency to refer CD Patients to centers of excellence where physicians with specific CD experience can confirm diagnosis, advise on disease management, and outline a treatment plan. Correct and timely diagnosis of the disease may improve the prognosis of CD patients.
2. PATHOLOGY OF CASTLEMAN DISEASE
Toolkit Modules:
- Disease Overview
- Pathology of Castleman Disease
- Clinical Manifestations
- Important Differential Diagnoses
- Case Studies
To avoid a delay in the accurate diagnosis of suspected Castleman disease, an experienced pathologist is recommended.
Evaluation of a surgically excised lymph node is central to the diagnosis of Castleman, and is also instrumental in ruling out malignancy and other disorders.
Histopathologic interpretation and subtype classification should be performed in concert with several other considerations, including:
- Clinical presentation
- Evaluation of lab tests for inflammatory cytokines, especially IL-6
- Serologic and molecular tests for HHV8, HIV, Epstein-Barr virus, and Cytomegalovirus
In addition, clinical and serologic exclusion should be made of the following conditions:
- Autoimmune disorders
- Connective tissue disorders
- Rheumatoid arthritis
- Other similar disorders
Hyaline Vascular Variant of Castleman Disease
The Most prominent characteristics of the hyaline vascular variant of Caslteman Disease include the following:
- Follicles that are regressed, or depleted of germinal center cells
- Mantle zones that are expanded with small lymphocytes arranged concentrically in an “onion skin” fashion
Additionally, the biopsy should reveal an interfollicular region that is expanded, with the following features:
- Prominent hyalinized blood vessels
- Myoid cells
- Dendritic reticulum cells
- Predominantly small T‐lymphocytes
- Focal Aggregates of plasmacytoid dendritic cells
Other histopathologic features of HV-CD include:
- A“lollipop” appearance (hyalinized blood vessels penetrating the follicles with concentric rimming of mantle zone lymphocytes)
- Expanded, dysplastic follicular dendritic cell networks
- Closed sinusoids
- Vascular proliferation and permeability
- Follicular mantle cells that may show co-expression of CD5 and CD20
By molecular analysis, HV-CD has shown:
- Lymphocytes are polyclonal
- Follicular dendritic cells have moderate to strong expression of EGFR
Plasma Cell Variant of CD (PC‐CD)
The most prominent characteristics of PC-CD include the following:
- Lymph nodes that show preserved architecture with hyperplastic follicles
- Increased interfollicular plasma cells, which are usually polyclonal but may be monotypic
- Plasma cells that, when monotypic, are usually lambda light chain restricted, IgG Or IgA, especially in PC-CD-associated POEMS syndrome (Polyneuropathy, Organomegaly, Endocrino pathy, Monoclonal protein, and Skin changes)
- Rare instances of monoclonality, which may lead to lymphoma
- Follicles that often contain hyperplastic germinal centers, but may also show regressed features
Histopathologic features are not specific to the plasma cell variant of CD, and can be seen in reactive lymphadenopathies including, but not limited to:
- Infections
- Autoimmune diseases
- Collagen Vascular and mixed connective tissue diseases
- Rheumatoid Arthritis with certain toxins
- HIV-related lymphadenopathy
These diseases should be excluded before attributing morphologic changes to PC-CD.
3. CLINICAL MANIFESTATIONS
Toolkit Modules:
- Disease Overview
- Pathology of Castleman Disease
- Clinical Manifestations
- Important Differential Diagnoses
- Case Studies
Signs and symptoms of CD are determined by several factors including:
- Disease extent (unicentric vs multicentric)
- Pathology type (hyaline vascular vs plasma cell)
- HIV status
- Extent of IL-6 secretion
- Associated immune phenomena
- Overlap with POEMS syndrome
With unicentric CD, clinicians can typically expect to observe:
- 1 lymph node station affected
- A mediastinal mass (alternate sites include intra-abdominal masses or involvement of cervical, axillary, and inguinal nodes).
- Asymptomatic patients, unless a compression on neurovascular site or other organs cause symptoms
- Patients who are mostly HIV negative with a hyaline vascular pathology and a lack of systemic symptoms or laboratory abnormalities reflecting excess IL‐6 Secretion
With multicentric CD, clinicians can typically expect to observe:
- Multiple lymph node stations affected
- Generalized lymphadenopathy
- 80% frequency of liver enlargement and 65% frequency of spleen enlargement
- PC‐variant histology
- Symptoms including fever, night sweats, fatigue, anorexia, and weight loss
Disorders associated with MCD include:
- Decreased albumin production
- Edema
- Pleural effusion
- Ascites
- Venous thrombosis
- Hemangiomata
- Skin lesions
- POEMS (NOTE: POEMS is associated with endocrine abnormalities, monoclonal gammopathy, sclerotic bone lesions and, in some cases, sensory, glove and stocking neuropathy)
Increased frequency of clonal hematologic disorders could include:
- Myeloma
- Amyloidosis
- Laboratory findings for MCD include:
- Anemia or thrombocytopenia
- Elevated ESR
- Increased C‐reactive protein
- Increased IL-6
- Increased fibrinogen
- Proteinuria
- Abnormal thyroid function tests
- Hypergammaglobulinemia
- Thrombocytosis
- Frequently, elevated plasma VEGF
- Low titer of antinuclear antibodies in about 30% of patients
4. IMPORTANT DIFFERENTIAL DIAGNOSES
Toolkit Modules:
- Disease Overview
- Pathology of Castleman Disease
- Clinical Manifestations
- Important Differential Diagnoses
- Case Studies
The diagnosis of Castleman disease is a diagnosis of exclusion. The most relevant differential diagnoses can be case specific, weighing various clinical factors against histopathological findings. More specific differential diagnostic criteria are covered in the Case Studies section of this toolkit. However, the following are common diseases which are to be excluded when Castleman disease is suspected:
- Follicular hyperplasia
- Follicular lymphoma
- HIV lymphadenopathy
- Mantle cell lymphoma
- Progressive transformation of germinal centers
5. CASE STUDIES
Toolkit Modules:
- Disease Overview
- Pathology of Castleman Disease
- Clinical Manifestations
- Important Differential Diagnoses
- Case Studies
A series of case study presentations by:
Jan Delabie, M.D., Ph.D., Professor, Department of Pathology, University of Toronto; Toronto, Canada.
Ahmet Dogan, M.D., Ph.D., Chief of Hematopathology, Memorial Sloan Kettering Cancer Center, New York; New York, USA.
Falko Fend, M.D., Professor and Department Chief, Institute of Pathology, University Hospital and Comprehensive Cancer Center, Tuebingen Eberhard-Karls-University; Tuebingen, Germany.
Case 1:
https://youtu.be/_Yfcs9XF6ds
Case 2:
https://youtu.be/sxDUf6Hrnh4
Case 3:
https://youtu.be/f5k1UnzOr_E
Case 4:
https://youtu.be/jZfnEMef30w
Case 5:
https://youtu.be/KiXSGXNgqoM
Case 6:
https://youtu.be/OCeg7O1LjMI
Case 7:
https://youtu.be/UasizDXAuaA