KSHV/HHV8-associated multicentric Castleman disease
Haematolymphoid Tumours (5th ed.)
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Primary Author(s)*
Sudha Arumugam, MD
Cancer Category / Type
Multicentric Castleman Disease
Cancer Sub-Classification / Subtype
None
Definition / Description of Disease
Castleman disease was initially described in 1956 by Castleman et al, who reported on 13 cases of localized mediastinal lymphoid proliferations in asymptomatic patients.[1] It is now recognized that there are different morphologic variants (hyaline vascular, plasma cell/plasmablastic, and mixed or transitional) as well as clinical forms (unicentric and multicentric) classified under the broad clinicopathologic syndrome termed Castleman disease.[2] Multicentric Castleman Disease is a rare clinicopathologic entity encompassing a group of systemic polyclonal lymphoproliferative disorders. It belongs to the spectrum of HHV8-associated lymphoproliferative disorders in which there is a proliferation of morphologically benign lymphocytes, plasma cells, and vessels due to excessive production of cytokines, IL6 features prominently amongst these.[3]Multicentric Castleman disease is idiopathic in HIV-negative and HHV8-negative patients.
Synonyms / Terminology
Angio follicular lymph-node hyperplasia
Giant node hyperplasia
Epidemiology / Prevalence
HHV8 Positive Multicentric Castleman Disease occurs in immunosuppressed patients across all ethnic groups, particularly in association with HIV/AIDS. [3] Immunocompetent individuals may be affected with the disease in HHV8 endemic areas such as sub-Saharan Africa and Mediterranean countries. In cases where HIV was acquired via sexual transmission, there is a strong association with the development of HHV8-positive MCD, men are predominantly affected.
Clinical Features
| Signs and Symptoms | Progressive lymphadenopathy
Splenomegaly or hepatosplenomegaly Fever Night sweats Fatigue Weight loss Respiratory symptoms Coincident Kaposi Sarcoma or HHV8-positive diffuse large B-cell lymphoma Skin rash |
| Laboratory Findings | Anemia
Thrombocytopenia Hypoalbuminemia Hypogammaglobinemia Elevated C-reactive protein |
Sites of Involvement
Multicentric Castleman Disease affects multiple lymph node sites, predominantly in the cervical region and commonly involves the spleen.[4]
Morphologic Features
HHV8-infected plasmablasts are the characteristic features of HHV8 Multicentric Castleman disease.[4] Plasmablasts are present in the lymph node and spleen.[2] The B cell follicles of lymph nodes shows varying degree of hyalinization and involution of germinal centers with prominent mantle zones that may intrude and efface the germinal centers.[3] Follicles may show onion skinning or widened concentric rings of mantle zone lymphocytes along with prominent penetrating venules, these findings are typical of Castleman disease.[3] Variable numbers of medium to large plasmablasts with amphophilic cytoplasm and eccentrically placed nuclei can be found among the mantle zone cells and adjacent interfollicular regions.[3] Sheets of mature plasma cells may be seen expanding the interfollicular region, some such cells may display cytoplasmic inclusions (Russell bodies) or crystalline forms.[3] With disease progression, the plasmablasts increase in number and may coalesce to form clusters.[3] If the disease proceeds to become HHV8-positive diffuse large B-cell lymphoma, NOS these clusters may expand clonally to form sheets of lymphoma cells that efface the normal follicular architecture.[3] Plasmablastic aggregates that develop during disease progression may be oligoclonal or monoclonal.
Immunophenotype
| Finding | Marker |
|---|---|
| Positive (universal) | HHV 8 LANA 1, strong c IgM expression with lambda light chain restriction, CD20+/-, CD 79a -/+ [3] |
| Positive (subset) | Viral IL-6 [3] |
| Negative (universal) | CD 138, PAX 5, CD38-/+, CD27, EBV encoded small RNA [3] |
| Negative (subset) | None |
Chromosomal Rearrangements (Gene Fusions)
Put your text here and fill in the table
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE t(9;22)(q34;q11.2) | EXAMPLE 3'ABL1 / 5'BCR | EXAMPLE der(22) | EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference) |
Yes | No | Yes | EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the previous version of the page. Please incorporate above.No known recurrent abnormalities
Individual Region Genomic Gain / Loss / LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)
| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE
7 |
EXAMPLE Loss | EXAMPLE
chr7:1- 159,335,973 [hg38] |
EXAMPLE
chr7 |
Yes | Yes | No | EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE
8 |
EXAMPLE Gain | EXAMPLE
chr8:1-145,138,636 [hg38] |
EXAMPLE
chr8 |
No | No | No | EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference). |
editv4:Individual Region Genomic Gain / Loss / LOHThe content below was from the previous version of the page. Please incorporate above.No known recurrent abnormalities
Characteristic Chromosomal Patterns
Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
editv4:Characteristic Chromosomal PatternsThe content below was from the previous version of the page. Please incorporate above.No known recurrent abnormalities
Gene Mutations (SNV / INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)
| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV / INDEL)The content below was from the previous version of the page. Please incorporate above.No known recurrent abnormalities
Epigenomic Alterations
No known recurrent abnormalities
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Can include references in the table.)
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
editv4:Genes and Main Pathways InvolvedThe content below was from the previous version of the page. Please incorporate above.No known recurrent abnormalities
Genetic Diagnostic Testing Methods
No known recurrent abnormalities
Familial Forms
Given there are no recurrent genetic abnormalities associated with MCD, no method can be recommended at present.
Additional Information
Put your text here
Links
None
References
- ↑ Castleman, Benjamin; et al. (1956-07). <822::aid-cncr2820090430>3.0.co;2-4 "Localized mediastinal lymph-node hyperplasia resembling thymoma". Cancer. 9 (4): 822–830. doi:10.1002/1097-0142(195607/08)9:4<822::aid-cncr2820090430>3.0.co;2-4. ISSN 0008-543X. Check date values in:
|date=(help) - ↑ 2.0 2.1 Chadburn, Amy; et al. (2017-02). "HHV8/KSHV-Positive Lymphoproliferative Disorders and the Spectrum of Plasmablastic and Plasma Cell Neoplasms". American Journal of Clinical Pathology. 147 (2): 171–187. doi:10.1093/ajcp/aqw218. ISSN 0002-9173. Check date values in:
|date=(help) - ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Swerdlow, Steven H.; et al. (2016-05-19). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". Blood. 127 (20): 2375–2390. doi:10.1182/blood-2016-01-643569. ISSN 0006-4971.
- ↑ 4.0 4.1 Balakrishna J. Castleman disease. PathologyOutlines.com website.https://www.pathologyoutlines.com/topic/lymphnodescastleman.html. Accessed November 24th, 2021.
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.
*Citation of this Page: “KSHV/HHV8-associated multicentric Castleman disease”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:KSHV/HHV8-associated_multicentric_Castleman_disease.