KSHV/HHV8-associated multicentric Castleman disease
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Multicentric Castleman Disease.
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
Primary Author(s)*
Sudha Arumugam, MD
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | B-cell lymphoid proliferations and lymphomas |
| Family | Tumour like lesions with B-cell predominance |
| Type | N/A |
| Subtype(s) | KSHV/HHV8-associated multicentric Castleman disease |
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 |
WHO Essential and Desirable Genetic Diagnostic Criteria
(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)
| WHO Essential Criteria (Genetics)* | |
| WHO Desirable Criteria (Genetics)* | |
| Other Classification |
*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.
Related Terminology
(Instructions: The table will have the related terminology from the WHO autocompleted.)
| Acceptable | |
| Not Recommended |
Gene Rearrangements
Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE: ABL1 | EXAMPLE: BCR::ABL1 | EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: Common (CML) | EXAMPLE: D, P, T | EXAMPLE: Yes (WHO, NCCN) | 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). BCR::ABL1 is generally favorable in CML (add reference). |
| EXAMPLE: CIC | EXAMPLE: CIC::DUX4 | EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. | EXAMPLE: t(4;19)(q25;q13) | EXAMPLE: Common (CIC-rearranged sarcoma) | EXAMPLE: D | EXAMPLE:
DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references). | |
| EXAMPLE: ALK | EXAMPLE: ELM4::ALK
|
EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. | EXAMPLE: N/A | EXAMPLE: Rare (Lung adenocarcinoma) | EXAMPLE: T | EXAMPLE:
Both balanced and unbalanced forms are observed by FISH (add references). | |
| EXAMPLE: ABL1 | EXAMPLE: N/A | EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. | EXAMPLE: N/A | EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) | EXAMPLE: D, P, T | ||
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the previous version of the page. Please incorporate above.
No known recurrent abnormalities
End of V4 Section
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE: 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 references). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add references). | |
| EXAMPLE:
17 |
EXAMPLE: Amp | EXAMPLE:
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb] |
EXAMPLE:
ERBB2 |
EXAMPLE: D, P, T | EXAMPLE:
Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined. | |
editv4:Individual Region Genomic Gain/Loss/LOHThe content below was from the previous version of the page. Please incorporate above.
No known recurrent abnormalities
End of V4 Section
Characteristic Chromosomal or Other Global Mutational Patterns
Put your text here and fill in the table (Instructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). | EXAMPLE: Common (Oligodendroglioma) | EXAMPLE: D, P | ||
| EXAMPLE:
Microsatellite instability - hypermutated |
EXAMPLE: Common (Endometrial carcinoma) | EXAMPLE: P, T | |||
editv4:Characteristic Chromosomal PatternsThe content below was from the previous version of the page. Please incorporate above.
No known recurrent abnormalities
End of V4 Section
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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:EGFR
|
EXAMPLE: Exon 18-21 activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (lung cancer) | EXAMPLE: T | EXAMPLE: Yes (NCCN) | EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references). |
| EXAMPLE: TP53; Variable LOF mutations
|
EXAMPLE: Variable LOF mutations | EXAMPLE: Tumor Supressor Gene | EXAMPLE: Common (breast cancer) | EXAMPLE: P | EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer. | |
| EXAMPLE: BRAF; Activating mutations | EXAMPLE: Activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (melanoma) | EXAMPLE: T | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, 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
End of V4 Section
Epigenomic Alterations
No known recurrent abnormalities
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete 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
End of V4 Section
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) - ↑ Jump up to: 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) - ↑ Jump up to: 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.
- ↑ Jump up to: 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 Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
*Citation of this Page: “KSHV/HHV8-associated multicentric Castleman disease”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/10/2025, https://ccga.io/index.php/HAEM5:KSHV/HHV8-associated_multicentric_Castleman_disease.