Gamma heavy chain disease

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Gamma Heavy Chain Disease.

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Primary Author(s)*

Manisha Brahmbhatt-Sutariya

Asst. Professor, Dept. of Pathology and Human Anatomy

Technical Supervisor, Clinical Genetics Laboratory

Loma Linda University, Medical Center, CA

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Plasma cell neoplasms and other diseases with paraproteins
Type Heavy chain diseases
Subtype(s) Gamma heavy chain disease

Definition / Description of Disease

  • gHCD is a B-cell neoplasm of lymphocytes, plasmacytoid lymphocytes and plasma cells[1][2]
  • Heterogenous clinical and pathological presentation[1]
  • Disseminated lymphoproliferative disorder is present in most patients at diagnosis[1][2][3]
  • It produces truncated monoclonal gamma (g) immunoglobulin (IgG) heavy chain that is incapable of associating with light chains[2]
  • Have concomitant autoimmune disease (mostly rheumatoid arthritis)
  • Three clusters of γ-HCD patients are identified:
    1. In around 60% of cases, γ-HCD is associated to disseminated lymphoma and patients typically have poor condition.
    2. In 25% of patients, γ-HCD is associated to localized lymphoma, affecting bone marrow, skin, thyroid, parotid, gastrointestinal or oropharynx tract (MALT lymphoma)
    3. In 15% of patients, γ-HCD is associated with autoimmune disease, mainly RA[4]

Synonyms / Terminology

  • Franklin disease[5]/ γHCD

Epidemiology / Prevalence

  • Incidence: Very rare, till date, ~only 200 cases have been reported in the literature[6]
  • Median age: 68 years (range, 42–87 years)[7]
  • Slight female predominance[3]

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)

Signs and Symptoms EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

EXAMPLE: B-symptoms (weight loss, fever, night sweats)

EXAMPLE: Fatigue

EXAMPLE: Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE: Cytopenias

EXAMPLE: Lymphocytosis (low level)


editv4:Clinical Features
The content below was from the old template. Please incorporate above.


Signs & Symptoms

  • Anorexia
  • Fever
  • Weakness
  • Weight loss
  • Recurrent bacterial infections
  • Concomitant autoimmune disorder
    • Rheumatoid arthritis
    • Myasthenia Gravis
    • Autoimmune cytopenia
    • Systemic Lupus Erythematosus
    • Thyroiditis
    • Vasculitis
    • Wasting
    • Sjögren syndrome
    • Thrombocytopenia
    • Autoimmune hemolytic anemia

Laboratory Findings

  • Anemia
  • Thrombocytopenia

Molecular Biology and Genetics

  • gHCD seems to be caused by deletions and/or insertions within the rearranged variable region genes (V), which could be a by-product of somatic hypermutation[2][8]


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[3]

Sites of Involvement

  • Bone marrow
  • Peripheral blood
  • Spleen
  • Liver
  • Lymph nodes
  • Waldeyer ring
  • Gastrointestinal tract
  • Extranodal sites

Morphologic Features

  • Mixed proliferation of various cell types:
    • Lymphocytes
    • Plasmacytoid lymphocytes
    • Plasma cells
    • Scattered immunoblasts
    • Reed–Sternberg cells
    • Eosinophils and histiocytes
  • Vascular proliferation may give rise to the histologic differential diagnosis of Hodgkin’s lymphoma or certain forms of T-cell lymphoma


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[6]

Immunophenotype

Finding Marker
Positive (B-cell lineage marker) CD19, CD20, CD79a, IgG (cytoplasmic) without light chain
Positive-Plasmacytoid cells MUM1/IRF4
Positive-Plasma cells CD38, CD138
Negative CD5, CD10


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[6]

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)
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  • No consistent gene fusions[9]


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)


  • N/A


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[10]

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. Do not delete table.)

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:Genomic Gain/Loss/LOH
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  • No consistent chromosomal gains or losses reported.
  • A single case report of trisomy of chromosome 7[11]


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[2][8]

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. Do not delete table.)

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 Aberrations / Patterns
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  • No consistent pattern reported

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 as 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. Do not delete table.)

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.

Epigenomic Alterations

  • No recurrent epigenomic alterations have been reported.

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete 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 Involved
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  • N/A

Genetic Diagnostic Testing Methods

  • Immunofixation (IF) is must and gold standard
  • Serum Protein Electrophoresis (SPEP)
  • Urine Electrophoresis
  • Morphology and immunophenotyping
  • MALDI-TOF MS could greatly improve the recognition of HCD because it directly detects the light chains and heavy chains and provides structural information about the proteins.


editUnassigned References
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[12][13][14]

Familial Forms

  • None reported

Additional Information

Some cases of gamma-HCD (γ-HCD) are concurrent with other lymphoid neoplasm have been reported in the literature and are listed below; treatment option varies with concurrent neoplasm


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[10]

Links

  • None

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)

  1. ↑ 1.0 1.1 1.2 Fermand, J. P.; et al. (1989-11). "Gamma heavy chain "disease": heterogeneity of the clinicopathologic features. Report of 16 cases and review of the literature". Medicine. 68 (6): 321–335. ISSN 0025-7974. PMID 2509855. Check date values in: |date= (help)
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Ramasamy, I.; et al. (2018). "Two Cases of γ-Heavy Chain Disease and a Review of the Literature". Case Reports in Hematology. 2018: 4832619. doi:10.1155/2018/4832619. ISSN 2090-6560. PMC 6109557. PMID 30186642.
  3. ↑ 3.0 3.1 3.2 Wahner-Roedler, Dietlind L.; et al. (2003-07). "Gamma-heavy chain disease: review of 23 cases". Medicine. 82 (4): 236–250. doi:10.1097/01.md.0000085058.63483.7f. ISSN 0025-7974. PMID 12861101. Check date values in: |date= (help)
  4. ↑ Danic, Gwenvaël; et al. (2021-03-17). "Gamma heavy chain disease associated with rheumatoid arthritis: a case report". Journal of Medical Case Reports. 15 (1): 121. doi:10.1186/s13256-021-02696-7. ISSN 1752-1947. PMC 7968189 Check |pmc= value (help). PMID 33726782 Check |pmid= value (help).
  5. ↑ Franklin, E. C.; et al. (1964-09). "HEAVY CHAIN DISEASE- A NEW DISORDER OF SERUM GAMMA-GLOBULINS : REPORT OF THE FIRST CASE". The American Journal of Medicine. 37: 332–350. doi:10.1016/0002-9343(64)90191-3. ISSN 0002-9343. PMID 14209281. Check date values in: |date= (help)
  6. ↑ 6.0 6.1 6.2 Munshi, Nikhil C.; et al. (2008-04-24). "Case records of the Massachusetts General Hospital. Case 13-2008. A 46-year-old man with rheumatoid arthritis and lymphadenopathy". The New England Journal of Medicine. 358 (17): 1838–1848. doi:10.1056/NEJMcpc0800959. ISSN 1533-4406. PMID 18434654.
  7. ↑ Zhou, Hebing; et al. (2016-06). "T cell receptor rearrangements in a patient with γ-heavy chain disease: A case report". Oncology Letters. 11 (6): 4147–4151. doi:10.3892/ol.2016.4515. ISSN 1792-1074. PMC 4888291. PMID 27313757. Check date values in: |date= (help)
  8. ↑ 8.0 8.1 Goossens, T.; et al. (1998-03-03). "Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease". Proceedings of the National Academy of Sciences of the United States of America. 95 (5): 2463–2468. doi:10.1073/pnas.95.5.2463. ISSN 0027-8424. PMC 19376. PMID 9482908.CS1 maint: PMC format (link)
  9. ↑ Witzig, Thomas E.; et al. (2002-06). "Heavy chain disease". Current Treatment Options in Oncology. 3 (3): 247–254. doi:10.1007/s11864-002-0014-3. ISSN 1527-2729. PMID 12057070. Check date values in: |date= (help)
  10. ↑ 10.0 10.1 Singer, Sara; et al. (2020-08). "Heavy Lifting: Nomenclature and Novel Therapy for Gamma Heavy Chain Disease and Other Heavy Chain Disorders". Clinical Lymphoma, Myeloma & Leukemia. 20 (8): 493–498. doi:10.1016/j.clml.2020.02.020. ISSN 2152-2669. PMID 32245744 Check |pmid= value (help). Check date values in: |date= (help)
  11. ↑ O'Conor, G. T.; et al. (1985-02-01). "Gamma heavy chain disease: report of a case associated with trisomy of chromosome 7". Cancer Genetics and Cytogenetics. 15 (1–2): 1–5. doi:10.1016/0165-4608(85)90125-6. ISSN 0165-4608. PMID 3917846.
  12. ↑ Mrosewski, Ingo; et al. (2020-01-01). "Gamma Heavy Chain Disease - Diagnostic Challenges in an Unusual Case and a Brief Synopsis of the Current Literature". Clinical Laboratory. 66 (1). doi:10.7754/Clin.Lab.2019.190623. ISSN 1433-6510. PMID 32013371 Check |pmid= value (help).
  13. ↑ Thoren, Katie L.; et al. (2020-03). "Identification of gamma heavy chain disease using MALDI-TOF mass spectrometry". Clinical Biochemistry. 77: 57–61. doi:10.1016/j.clinbiochem.2019.12.010. ISSN 1873-2933. PMC 7046309 Check |pmc= value (help). PMID 31884198. Check date values in: |date= (help)
  14. ↑ Ho, Y. H.; et al. (2014-08). "Gamma heavy chain disease: cytological diagnosis of a rare lymphoid malignancy facilitated by correlation with key laboratory findings". Cytopathology: Official Journal of the British Society for Clinical Cytology. 25 (4): 270–273. doi:10.1111/cyt.12126. ISSN 1365-2303. PMID 25180407. Check date values in: |date= (help)

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: “Gamma heavy chain disease”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Gamma_heavy_chain_disease.

Other Sections

Gene Mutations (SN V/INDEL)


  • g-HCD lacks MYD88 L265p mutation associated with lymphoplasmacytic lymphoma, hence gHCD should no longer be considered a variant of LPL[1]
  • Deletions and insertions account for approximately 6% of somatic point mutations introduced into rearranged VH region genes of germinal B cells[2].
  • No sequencing data is available till date.
  1. ↑ Hamadeh, Fatima; et al. (2014-09). "Gamma heavy chain disease lacks the MYD88 L265p mutation associated with lymphoplasmacytic lymphoma". Haematologica. 99 (9): e154–155. doi:10.3324/haematol.2014.108688. ISSN 1592-8721. PMC 4562547. PMID 24859878. Check date values in: |date= (help)
  2. ↑ Alexander, A.; et al. (1988-10-XX). "Gamma heavy chain disease in man. Genomic sequence reveals two noncontiguous deletions in a single gene". The Journal of Clinical Investigation. 82 (4): 1244–1252. doi:10.1172/JCI113722. ISSN 0021-9738. PMC 442675. PMID 3139711. Check date values in: |date= (help)CS1 maint: PMC format (link)
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