Gamma heavy chain disease

Haematolymphoid Tumours (5th ed.)

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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

• HAEM4:Mature B-Cell Neoplasms

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
• Heterogenous clinical and pathological presentation
• Disseminated lymphoproliferative disorder is present in most patients at diagnosis
• It produces truncated monoclonal gamma (g) immunoglobulin (IgG) heavy chain that is incapable of associating with light chains
• 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

Synonyms / Terminology

• Franklin disease/ γHCD

Epidemiology / Prevalence

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

Clinical Features

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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

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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

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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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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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Chromosomal Rearrangements (Gene Fusions)

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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

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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Individual Region Genomic Gain / Loss / LOH

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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).

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

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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 Aberrations / Patterns

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• No consistent pattern reported

Gene Mutations (SNV / INDEL)

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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

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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.

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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

• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL)
• DLBCL-diffuse large B cell Lymphoma
• LCPD-lymphoplasma cell proliferative disorder
• Lymphoplasmacytic Lymphoma (LPL)
• MALT -mucosa-associated lymphoid tissue
• MDS-myelodysplastic syndrome
• MGUS-monoclonal gammopathy of undetermined Significance
• SDRPSBCL-splenic diffuse red pulp small B-cell lymphoma
• SMZL-splenic marginal zone lymphoma
• T-LGLL-T-cell large granular lymphocytic leukemia

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Links

• None

References

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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 12/13/2023, 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
• Deletions and insertions account for approximately 6% of somatic point mutations introduced into rearranged VH region genes of germinal B cells.
• No sequencing data is available till date.