HAEM5:Monoclonal immunoglobulin deposition disease

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:Light Chain and Heavy Chain Deposition 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)*

Chen Yang, MD, PhD, University of Michigan

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	Diseases with monoclonal immunoglobulin deposition
Subtype(s)	Monoclonal immunoglobulin deposition disease

Definition / Description of Disease

Light Chain and Heavy Chain Deposition Disease is defined as follows:

• Systemic disorder with non-amyloid deposits of monoclonal immunoglobulin (Ig) in various organs
• Underlying diseases are HAEM4:Plasma Cell Neoplasms (PCN, >95%) or lymphoplasmacytic neoplasms (2-3%)
• 20-35% have non-smoldering HAEM5:Plasma cell myeloma / multiple myeloma (PCM), and rest (65-75%) have smoldering plasma cell myeloma or Monoclonal Gammopathy of Uncertain Significance (MGUS)/monoclonal gammopathy of renal significance (MGRS)

Synonyms / Terminology

• Randall type monoclonal immunoglobulin deposition disease
• Light chain deposition disease (LCDD)
• heavy chain deposition disease (HCDD)
• light and heavy chain deposition disease (LHCDD)

Epidemiology / Prevalence

The following epidemiologic features have been observed:

• Vary rare
• Median age: 56-58 years (range: 20-91)
• 60% are men
• No ethnic difference
• Deposited Ig can be light chain (LCDD, ~80%), heavy chain (HCDD, ~10%), or both (LHCDD, ~10%)

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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The following clinical and laboratory findings may be seen:

Signs & Symptoms

• Organ dysfunction resulting from systemic Ig deposition
• Renal dysfunction (renal insufficiency, proteinuria, hematuria, and hypertension) in almost all cases
• Renal failure eventually without treatment
• Extrarenal symptoms (10-35%) from IG deposition in heart, liver, peripheral nerves, lung, skin, blood vessels, and occasionally joints
• Diastolic heart failure and atrial arrhythmias if heart involved
• Hepatomegaly, portal hypertension and liver failure if liver involved
• Cough, oxygen desaturation and dyspnea if lung involved
• Peripheral and autonomic neuropathy if nerve involved

Laboratory findings

• Abnormal serum free light chain ratio in almost all cases
• M-protein detected on SPEP in majority (70-85%) cases
• IgG followed by light chain, IgA and IgM, as the most common monoclonal Ig detected in serum
• The tissue immunoglobulin deposits can differ from the monoclonal Ig in serum
• Hypocomplementemia in HCDD, due to complement fixation by IgG3 and IgG1 subclasses
• Septal thickening on echocardiogram if heart involved
• Elevated liver function test results if liver involved

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Sites of Involvement

The following anatomic sites of involvement have been reported:

• Kidney is nearly always involved
• Extrarenal organs (heart, liver, peripheral nerves, lung, skin, and blood vessels) involve in 10-35% cases
• Extrarenal involvement is more common in LCDD with PCM
• Basement membranes and elastic and collagen fibers are the prominent deposition sites

Morphologic Features

• Most cases are associated with PCM or MGUS, and rarely with HAEM5:Lymphoplasmacytic lymphoma, marginal zone lymphoma, or HAEM5:Chronic lymphocytic leukaemia/small lymphocytic lymphoma
• The smooth, ribbon-like linear Ig deposits consist of Congo red-negative amorphous eosinophilic material that is non-amyloid and non-fibrillary
• Deposition of Ig is mostly found on renal biopsies but can be observed in bone marrow and other tissues
• The renal biopsy typically (in 2/3 of cases) shows nodular sclerosing glomerulonephritis
• Ig predominantly deposits along tubular basement membranes (TBM) and glomerular basement membranes (GBM) under kidney immunofluorescence stain

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

editv4:Immunophenotype

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Findings are similar to those of the underlying condition (e.g., Plasma Cell Neoplasm, HAEM5:Lymphoplasmacytic lymphoma). Additional findings may include the following:

• The plasma cells in bone marrow may exhibit an aberrant kappa/lambda ratio
• Kappa light chains, especially VκIV variable region, are overrepresented (68-80%) in LCDD
• Gamma chains are most common in HCDD
• Deletion of the CH1 constant domain leads to premature secretion and tissue deposition of heavy chain in HCDD
• Somatic mutations of the variable regions of light chain or heavy chain increase the hydrophobicity and hence the propensity for tissue deposition of Ig

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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 Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	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)

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• There is limited information on the genomic abnormalities of the plasma cells in light chain and heavy chain deposition disease
• Patients with PCM presumably have similar genomic abnormalities to myelomas without Ig deposition, perhaps with a different prevalence
• In one study, t(11;14)(q13;q32) IGH/CCND1 fusion is detected as the most common fusion (nearly 50%), comparing to only 15-20% in myeloma without Ig deposition

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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)

• Due to limited studies, no genetic abnormalities are prognostic or predictive of treatment response
• FISH detection of the potentially frequent t(11;14) IGH/CCND1 fusion in association with BCL2 overexpression may help guide the application of BCL2 blocking agents including venetoclax

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Individual Region Genomic Gain/Loss/LOH

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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:Genomic Gain/Loss/LOH

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• Findings are similar to those of the underlying condition (e.g., Plasma Cell Neoplasm, HAEM5:Lymphoplasmacytic lymphoma)

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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 Aberrations / Patterns

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• Patients with PCM presumably have similar genomic abnormalities to myelomas without Ig deposition, perhaps with a different prevalence
• In one study, t(11;14)(q13;q32) IGH/CCND1 fusion is detected as the most common fusion (nearly 50%), comparing to only 15-20% in myeloma without Ig deposition
• In the same study, hyperdiploidy is detected only at 16%, comparing to ~60% in myeloma without Ig deposition

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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)

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• Findings are similar to those of the underlying condition (e.g., Plasma Cell Neoplasm, HAEM5:Lymphoplasmacytic lymphoma)

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Epigenomic Alterations

• Findings are similar to those of the underlying condition (e.g., Plasma Cell Neoplasm, HAEM5:Lymphoplasmacytic lymphoma)

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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• Findings are similar to those of the underlying condition (e.g., Plasma Cell Neoplasm, HAEM5:Lymphoplasmacytic lymphoma)

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Genetic Diagnostic Testing Methods

Testing methods include those needed to diagnose the underlying condition, as well as those specifically needed to detect the offending Ig in liquid samples and tissues. The following methods of testing have been reported:

• Diagnosis relies on detection of monoclonal Ig deposition in tissues biopsy; fine needle aspiration is not enough for diagnosis
• Because kidney is almost always affected, detecting linear Ig deposits predominantly along TBM and GBM under immunofluorescence (IF) and/or electron microscopy studies of the kidney biopsy is diagnostic
• Diagnosis in other tissues relies more on immunohistochemistry, as electron microscopy is rarely used
• Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), immunofixation, and serum free light-chain (SFLC), should be performed to identify the monoclonal Ig; abnormal rates are 64% by SPEP, 68% UPEP, and 99–100% by SFLC
• Bone marrow aspiration and biopsy should be routinely performed to identify the lymphoproliferative clone
• Chromosome analysis and fluorescent in situ hybridization (FISH) were performed only for a small portion of cases historically but are helpful for clonal identification

Familial Forms

• N/A

Additional Information

• Survival improves with early diagnosis and proteasome inhibitor (PI)-based treatment, autologous stem cell transplantation, and kidney transplantation
• Poor prognosis markers include old age, the presence of PCM, extrarenal (especially cardiac) involvement, poor response to initial treatment
• Elimination or reduction of the underlying B-cell proliferative neoplasms to control the aberrant Ig deposition is crucial for preventing disease progression
• Kidney transplantation has a very high recurrence rate without controlling the monoclonal gammopathy

Links

• HAEM4:Monoclonal Immunoglobulin Deposition Diseases
• HAEM5:Immunoglobulin-related (AL) amyloidosis
• Plasma Cell Myeloma
• HAEM5:Non-IgM monoclonal gammopathy of undetermined significance

References

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Notes

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Prior Author(s):

*Citation of this Page: “Monoclonal immunoglobulin deposition disease”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/10/2025, https://ccga.io/index.php/HAEM5:Monoclonal_immunoglobulin_deposition_disease.