HAEM4Backup:Light Chain and Heavy Chain Deposition Disease

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Primary Author(s)*

Chen Yang, MD, PhD, University of Michigan

Cancer Category/Type

Cancer Sub-Classification / Subtype

Definition / Description of Disease

Light Chain and Heavy Chain Deposition Disease is defined as follows[1][2][3][4]:

  • Systemic disorder with non-amyloid deposits of monoclonal immunoglobulin (Ig) in various organs
  • Underlying diseases are Plasma Cell Neoplasms (PCN, >95%) or lymphoplasmacytic neoplasms (2-3%)
  • 20-35% have non-smoldering Plasma Cell 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[5][6][7][8]:

  • 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

The following clinical and laboratory findings may be seen[5][6][7][8][9][10]:

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

Sites of Involvement

The following anatomic sites of involvement have been reported[6][7][8][9]:

  • 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[5], and rarely with Lymphoplasmacytic Lymphoma, marginal zone lymphoma, or Chronic Lymphocytic Leukemia/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[6]

Immunophenotype

Findings are similar to those of the underlying condition (e.g., Plasma Cell Neoplasm, Lymphoplasmacytic Lymphoma). Additional findings may include the following[6][8]:

  • 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

Chromosomal Rearrangements (Gene Fusions)

  • 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[8], 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

Characteristic Chromosomal Aberrations / Patterns

  • Patients with PCM presumably have similar genomic abnormalities to myelomas without Ig deposition, perhaps with a different prevalence
  • In one study[8], 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[8], hyperdiploidy is detected only at 16%, comparing to ~60% in myeloma without Ig deposition

Genomic Gain/Loss/LOH

Gene Mutations (SNV/INDEL)

Epigenomics (Methylation)

Genes and Main Pathways Involved

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[5][6][7][8][9]:

  • 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

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • 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[11][12][13]

Familial Forms

  • N/A

Other Information

  • Survival improves with early diagnosis and proteasome inhibitor (PI)-based treatment, autologous stem cell transplantation, and kidney transplantation[10][14]
  • Poor prognosis markers include old age, the presence of PCM, extrarenal (especially cardiac) involvement, poor response to initial treatment[7][15]
  • Elimination or reduction of the underlying B-cell proliferative neoplasms to control the aberrant Ig deposition is crucial for preventing disease progression[14][10]
  • Kidney transplantation has a very high recurrence rate without controlling the monoclonal gammopathy[16]

Links


References

(use "Cite" icon at top of page)

  1. ↑ McKenna RW, et al., (2017). Plasma cell neoplasms: Light chain and heavy chain deposition diseases, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p255-256.
  2. ↑ Sethi, Sanjeev; et al. (2018-07). "The Complexity and Heterogeneity of Monoclonal Immunoglobulin-Associated Renal Diseases". Journal of the American Society of Nephrology: JASN. 29 (7): 1810–1823. doi:10.1681/ASN.2017121319. ISSN 1533-3450. PMC 6050917. PMID 29703839. Check date values in: |date= (help)
  3. ↑ Leung, Nelson; et al. (2019-01). "The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group". Nature Reviews. Nephrology. 15 (1): 45–59. doi:10.1038/s41581-018-0077-4. ISSN 1759-507X. PMC 7136169 Check |pmc= value (help). PMID 30510265. Check date values in: |date= (help)
  4. ↑ Leung, Nelson; et al. (2021-05-20). "Monoclonal Gammopathy of Renal Significance". The New England Journal of Medicine. 384 (20): 1931–1941. doi:10.1056/NEJMra1810907. ISSN 1533-4406. PMID 34010532 Check |pmid= value (help).
  5. ↑ 5.0 5.1 5.2 5.3 Pozzi, Claudio; et al. (2003-12). "Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 42 (6): 1154–1163. doi:10.1053/j.ajkd.2003.08.040. ISSN 1523-6838. PMID 14655186. Check date values in: |date= (help)
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Nasr, Samih H.; et al. (2012-02). "Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution". Clinical journal of the American Society of Nephrology: CJASN. 7 (2): 231–239. doi:10.2215/CJN.08640811. ISSN 1555-905X. PMID 22156754. Check date values in: |date= (help)
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Joly, Florent; et al. (2019-02-07). "Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study". Blood. 133 (6): 576–587. doi:10.1182/blood-2018-09-872028. ISSN 1528-0020. PMID 30578255.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Kourelis, Taxiarchis V.; et al. (2016-11). "Outcomes of patients with renal monoclonal immunoglobulin deposition disease". American Journal of Hematology. 91 (11): 1123–1128. doi:10.1002/ajh.24528. ISSN 1096-8652. PMID 27501122. Check date values in: |date= (help)
  9. ↑ 9.0 9.1 9.2 Mohan, Meera; et al. (2017-08). "Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease". American Journal of Hematology. 92 (8): 739–745. doi:10.1002/ajh.24756. ISSN 1096-8652. PMID 28383130. Check date values in: |date= (help)
  10. ↑ 10.0 10.1 10.2 Sayed, Rabya H.; et al. (2015-12-24). "Natural history and outcome of light chain deposition disease". Blood. 126 (26): 2805–2810. doi:10.1182/blood-2015-07-658872. ISSN 1528-0020. PMC 4732758. PMID 26392598.
  11. ↑ Szita, Virág Réka; et al. (2022). "Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers". Pathology oncology research: POR. 28: 1610276. doi:10.3389/pore.2022.1610276. ISSN 1532-2807. PMC 8918485 Check |pmc= value (help). PMID 35295611 Check |pmid= value (help).
  12. ↑ Bal, Susan; et al. (2022). "Multiple myeloma with t(11;14): unique biology and evolving landscape". American Journal of Cancer Research. 12 (7): 2950–2965. ISSN 2156-6976. PMC 9360221 Check |pmc= value (help). PMID 35968339 Check |pmid= value (help).
  13. ↑ Chakraborty, Rajshekhar; et al. (2022-10). "How do we manage t(11;14) plasma cell disorders with venetoclax?". British Journal of Haematology. 199 (1): 31–39. doi:10.1111/bjh.18243. ISSN 1365-2141. PMID 35594184 Check |pmid= value (help). Check date values in: |date= (help)
  14. ↑ 14.0 14.1 Cohen, Camille; et al. (2015-11). "Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease". Kidney International. 88 (5): 1135–1143. doi:10.1038/ki.2015.201. ISSN 1523-1755. PMID 26176826. Check date values in: |date= (help)
  15. ↑ Angel-Korman, Avital; et al. (2020-04). "The Role of Kidney Transplantation in Monoclonal Ig Deposition Disease". Kidney International Reports. 5 (4): 485–493. doi:10.1016/j.ekir.2020.01.011. ISSN 2468-0249. PMC 7136323 Check |pmc= value (help). PMID 32274452 Check |pmid= value (help). Check date values in: |date= (help)
  16. ↑ Said, Samar M.; et al. (2018-07). "Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft". Kidney International. 94 (1): 159–169. doi:10.1016/j.kint.2018.01.028. ISSN 1523-1755. PMID 29716794. Check date values in: |date= (help)

Notes

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