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

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Gamma Heavy Chain Disease (gHCD)

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[3]

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]

Sites of Involvement

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

Morphologic Features[6]

  • 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

Immunophenotype[6]

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

Chromosomal Rearrangements (Gene Fusions)

  • No consistent gene fusions[9]

Characteristic Chromosomal Aberrations / Patterns

  • No consistent pattern reported

Genomic Gain/Loss/LOH[2][8]

  • No consistent chromosomal gains or losses reported.
  • A single case report of trisomy of chromosome 7[10]

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[11]
  • Deletions and insertions account for approximately 6% of somatic point mutations introduced into rearranged VH region genes of germinal B cells[12].
  • No sequencing data is available till date.

Epigenomics (Methylation)

  • No recurrent epigenomic alterations have been reported.

Genes and Main Pathways Involved

  • N/A

Diagnostic Testing Methods[13][14][15]

  • 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.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)[16]

  • N/A

Familial Forms

  • None reported

Other Information[16]

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

Links

  • None

References

  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. 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.
  11. 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)
  12. 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)
  13. 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).
  14. 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)
  15. 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)
  16. 16.0 16.1 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)

Notes

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