Bailey.Glen: Created page with "==Primary Author(s)== Chen Yang, MD, PhD, University of Michigan TOC ==Cancer Category/Type== [https://ccga.io/index.php/Mature_B-Cell_Neoplasms Mature B-cell neopla..."

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Created page with "==Primary Author(s)*== Chen Yang, MD, PhD, University of Michigan __TOC__ ==Cancer Category/Type== *[https://ccga.io/index.php/Mature_B-Cell_Neoplasms Mature B-cell neopla..."

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==Primary Author(s)*==

Chen Yang, MD, PhD, University of Michigan

__TOC__

==Cancer Category/Type==

*[https://ccga.io/index.php/Mature_B-Cell_Neoplasms Mature B-cell neoplasms]

==Cancer Sub-Classification / Subtype==

*[https://ccga.io/index.php/Monoclonal_Immunoglobulin_Deposition_Diseases Monoclonal immunoglobulin deposition disease]

==Definition / Description of Disease==
Light Chain and Heavy Chain Deposition Disease is defined as follows<ref>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.</ref><ref>{{Cite journal|last=Sethi|first=Sanjeev|last2=Rajkumar|first2=S. Vincent|last3=D'Agati|first3=Vivette D.|date=2018-07|title=The Complexity and Heterogeneity of Monoclonal Immunoglobulin-Associated Renal Diseases|url=https://pubmed.ncbi.nlm.nih.gov/29703839|journal=Journal of the American Society of Nephrology: JASN|volume=29|issue=7|pages=1810–1823|doi=10.1681/ASN.2017121319|issn=1533-3450|pmc=6050917|pmid=29703839}}</ref><ref>{{Cite journal|last=Leung|first=Nelson|last2=Bridoux|first2=Frank|last3=Batuman|first3=Vecihi|last4=Chaidos|first4=Aristeidis|last5=Cockwell|first5=Paul|last6=D'Agati|first6=Vivette D.|last7=Dispenzieri|first7=Angela|last8=Fervenza|first8=Fernando C.|last9=Fermand|first9=Jean-Paul|date=2019-01|title=The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group|url=https://pubmed.ncbi.nlm.nih.gov/30510265|journal=Nature Reviews. Nephrology|volume=15|issue=1|pages=45–59|doi=10.1038/s41581-018-0077-4|issn=1759-507X|pmc=7136169|pmid=30510265}}</ref><ref>{{Cite journal|last=Leung|first=Nelson|last2=Bridoux|first2=Frank|last3=Nasr|first3=Samih H.|date=2021-05-20|title=Monoclonal Gammopathy of Renal Significance|url=https://pubmed.ncbi.nlm.nih.gov/34010532|journal=The New England Journal of Medicine|volume=384|issue=20|pages=1931–1941|doi=10.1056/NEJMra1810907|issn=1533-4406|pmid=34010532}}</ref>:

*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<ref name=":0">{{Cite journal|last=Pozzi|first=Claudio|last2=D'Amico|first2=Marco|last3=Fogazzi|first3=Giovanni B.|last4=Curioni|first4=Simona|last5=Ferrario|first5=Franco|last6=Pasquali|first6=Sonia|last7=Quattrocchio|first7=Giacomo|last8=Rollino|first8=Cristiana|last9=Segagni|first9=Siro|date=2003-12|title=Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors|url=https://pubmed.ncbi.nlm.nih.gov/14655186|journal=American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation|volume=42|issue=6|pages=1154–1163|doi=10.1053/j.ajkd.2003.08.040|issn=1523-6838|pmid=14655186}}</ref><ref name=":2">{{Cite journal|last=Nasr|first=Samih H.|last2=Valeri|first2=Anthony M.|last3=Cornell|first3=Lynn D.|last4=Fidler|first4=Mary E.|last5=Sethi|first5=Sanjeev|last6=D'Agati|first6=Vivette D.|last7=Leung|first7=Nelson|date=2012-02|title=Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution|url=https://pubmed.ncbi.nlm.nih.gov/22156754|journal=Clinical journal of the American Society of Nephrology: CJASN|volume=7|issue=2|pages=231–239|doi=10.2215/CJN.08640811|issn=1555-905X|pmid=22156754}}</ref><ref name=":1">{{Cite journal|last=Joly|first=Florent|last2=Cohen|first2=Camille|last3=Javaugue|first3=Vincent|last4=Bender|first4=Sébastien|last5=Belmouaz|first5=Mohamed|last6=Arnulf|first6=Bertrand|last7=Knebelmann|first7=Bertrand|last8=Nouvier|first8=Mathilde|last9=Audard|first9=Vincent|date=2019-02-07|title=Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study|url=https://pubmed.ncbi.nlm.nih.gov/30578255|journal=Blood|volume=133|issue=6|pages=576–587|doi=10.1182/blood-2018-09-872028|issn=1528-0020|pmid=30578255}}</ref><ref name=":4" />:

*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<ref name=":0" /><ref name=":2" /><ref name=":1" /><ref name=":4" /><ref name=":3">{{Cite journal|last=Mohan|first=Meera|last2=Buros|first2=Amy|last3=Mathur|first3=Pankaj|last4=Gokden|first4=Neriman|last5=Singh|first5=Manisha|last6=Susanibar|first6=Sandra|last7=Jo Kamimoto|first7=Jorge|last8=Hoque|first8=Shadiqul|last9=Radhakrishnan|first9=Muthukumar|date=2017-08|title=Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease|url=https://pubmed.ncbi.nlm.nih.gov/28383130|journal=American Journal of Hematology|volume=92|issue=8|pages=739–745|doi=10.1002/ajh.24756|issn=1096-8652|pmid=28383130}}</ref><ref name=":5">{{Cite journal|last=Sayed|first=Rabya H.|last2=Wechalekar|first2=Ashutosh D.|last3=Gilbertson|first3=Janet A.|last4=Bass|first4=Paul|last5=Mahmood|first5=Shameem|last6=Sachchithanantham|first6=Sajitha|last7=Fontana|first7=Marianna|last8=Patel|first8=Ketna|last9=Whelan|first9=Carol J.|date=2015-12-24|title=Natural history and outcome of light chain deposition disease|url=https://pubmed.ncbi.nlm.nih.gov/26392598|journal=Blood|volume=126|issue=26|pages=2805–2810|doi=10.1182/blood-2015-07-658872|issn=1528-0020|pmc=4732758|pmid=26392598}}</ref>:

'''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<ref name=":2" /><ref name=":1" /><ref name=":4" /><ref name=":3" />:

*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<ref name=":0" />, 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<ref name=":2" />

==Immunophenotype==
Findings are similar to those of the underlying condition (e.g., [[Plasma Cell Neoplasms|Plasma Cell Neoplasm]], [[Lymphoplasmacytic Lymphoma]]). Additional findings may include the following<ref name=":2" /><ref name=":4" />:

*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<ref name=":4">{{Cite journal|last=Kourelis|first=Taxiarchis V.|last2=Nasr|first2=Samih H.|last3=Dispenzieri|first3=Angela|last4=Kumar|first4=Shaji K.|last5=Gertz|first5=Morie A.|last6=Fervenza|first6=Fernando C.|last7=Buadi|first7=Francis K.|last8=Lacy|first8=Martha Q.|last9=Erickson|first9=Stephen B.|date=2016-11|title=Outcomes of patients with renal monoclonal immunoglobulin deposition disease|url=https://pubmed.ncbi.nlm.nih.gov/27501122|journal=American Journal of Hematology|volume=91|issue=11|pages=1123–1128|doi=10.1002/ajh.24528|issn=1096-8652|pmid=27501122}}</ref>, 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<ref name=":4" />, 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<ref name=":4" />, hyperdiploidy is detected only at 16%, comparing to ~60% in myeloma without Ig deposition
*

==Genomic Gain/Loss/LOH==

*Findings are similar to those of the underlying condition (e.g., [[Plasma Cell Neoplasms|Plasma Cell Neoplasm]], [[Lymphoplasmacytic Lymphoma]])

==Gene Mutations (SNV/INDEL)==

*Findings are similar to those of the underlying condition (e.g., [[Plasma Cell Neoplasms|Plasma Cell Neoplasm]], [[Lymphoplasmacytic Lymphoma]])

==Epigenomics (Methylation)==

*Findings are similar to those of the underlying condition (e.g., [[Plasma Cell Neoplasms|Plasma Cell Neoplasm]], [[Lymphoplasmacytic Lymphoma]])

==Genes and Main Pathways Involved==

*Findings are similar to those of the underlying condition (e.g., [[Plasma Cell Neoplasms|Plasma Cell Neoplasm]], [[Lymphoplasmacytic Lymphoma]])

==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<ref name=":0" /><ref name=":2" /><ref name=":1" /><ref name=":4" /><ref name=":3" />:

*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<ref>{{Cite journal|last=Szita|first=Virág Réka|last2=Mikala|first2=Gábor|last3=Kozma|first3=András|last4=Fábián|first4=János|last5=Hardi|first5=Apor|last6=Alizadeh|first6=Hussain|last7=Rajnics|first7=Péter|last8=Rejtő|first8=László|last9=Szendrei|first9=Tamás|date=2022|title=Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers|url=https://pubmed.ncbi.nlm.nih.gov/35295611|journal=Pathology oncology research: POR|volume=28|pages=1610276|doi=10.3389/pore.2022.1610276|issn=1532-2807|pmc=8918485|pmid=35295611}}</ref><ref>{{Cite journal|last=Bal|first=Susan|last2=Kumar|first2=Shaji K.|last3=Fonseca|first3=Rafael|last4=Gay|first4=Francesca|last5=Hungria|first5=Vania Tm|last6=Dogan|first6=Ahmet|last7=Costa|first7=Luciano J.|date=2022|title=Multiple myeloma with t(11;14): unique biology and evolving landscape|url=https://pubmed.ncbi.nlm.nih.gov/35968339|journal=American Journal of Cancer Research|volume=12|issue=7|pages=2950–2965|issn=2156-6976|pmc=9360221|pmid=35968339}}</ref><ref>{{Cite journal|last=Chakraborty|first=Rajshekhar|last2=Bhutani|first2=Divaya|last3=Lentzsch|first3=Suzanne|date=2022-10|title=How do we manage t(11;14) plasma cell disorders with venetoclax?|url=https://pubmed.ncbi.nlm.nih.gov/35594184|journal=British Journal of Haematology|volume=199|issue=1|pages=31–39|doi=10.1111/bjh.18243|issn=1365-2141|pmid=35594184}}</ref>

==Familial Forms==

*N/A

==Other Information==

*Survival improves with early diagnosis and proteasome inhibitor (PI)-based treatment, autologous stem cell transplantation, and kidney transplantation<ref name=":5" /><ref name=":6">{{Cite journal|last=Cohen|first=Camille|last2=Royer|first2=Bruno|last3=Javaugue|first3=Vincent|last4=Szalat|first4=Raphael|last5=El Karoui|first5=Khalil|last6=Caulier|first6=Alexis|last7=Knebelmann|first7=Bertrand|last8=Jaccard|first8=Arnaud|last9=Chevret|first9=Sylvie|date=2015-11|title=Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease|url=https://pubmed.ncbi.nlm.nih.gov/26176826|journal=Kidney International|volume=88|issue=5|pages=1135–1143|doi=10.1038/ki.2015.201|issn=1523-1755|pmid=26176826}}</ref>
*Poor prognosis markers include old age, the presence of PCM, extrarenal (especially cardiac) involvement, poor response to initial treatment<ref name=":1" /><ref>{{Cite journal|last=Angel-Korman|first=Avital|last2=Stern|first2=Lauren|last3=Angel|first3=Yoel|last4=Sarosiek|first4=Shayna|last5=Menn-Josephy|first5=Hanni|last6=Francis|first6=Jean|last7=Ghai|first7=Sandeep|last8=Sloan|first8=J. Mark|last9=Sanchorawala|first9=Vaishali|date=2020-04|title=The Role of Kidney Transplantation in Monoclonal Ig Deposition Disease|url=https://pubmed.ncbi.nlm.nih.gov/32274452|journal=Kidney International Reports|volume=5|issue=4|pages=485–493|doi=10.1016/j.ekir.2020.01.011|issn=2468-0249|pmc=7136323|pmid=32274452}}</ref>
*Elimination or reduction of the underlying B-cell proliferative neoplasms to control the aberrant Ig deposition is crucial for preventing disease progression<ref name=":6" /><ref name=":5" />
*Kidney transplantation has a very high recurrence rate without controlling the monoclonal gammopathy<ref>{{Cite journal|last=Said|first=Samar M.|last2=Cosio|first2=Fernando G.|last3=Valeri|first3=Anthony M.|last4=Leung|first4=Nelson|last5=Sethi|first5=Sanjeev|last6=Salameh|first6=Hassan|last7=Cornell|first7=Lynn D.|last8=Fidler|first8=Mary E.|last9=Alexander|first9=Mariam P.|date=2018-07|title=Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft|url=https://pubmed.ncbi.nlm.nih.gov/29716794|journal=Kidney International|volume=94|issue=1|pages=159–169|doi=10.1016/j.kint.2018.01.028|issn=1523-1755|pmid=29716794}}</ref>

==Links==

*[[Monoclonal Immunoglobulin Deposition Diseases]]
*[[Primary Amyloidosis]]
*[[Plasma Cell Myeloma|Plasma Cell Myeloma]]
*[[Non-IgM Monoclonal Gammopathy of Undetermined Signiﬁcance]]

<br />

==References==
(use "Cite" icon at top of page)
<references />
==Notes==
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HAEM4Backup:Light Chain and Heavy Chain Deposition Disease - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Chen Yang, MD, PhD, University of Michigan __TOC__ ==Cancer Category/Type== *[https://ccga.io/index.php/Mature_B-Cell_Neoplasms Mature B-cell neopla..."

Bailey.Glen: Created page with "==Primary Author(s)== Chen Yang, MD, PhD, University of Michigan TOC ==Cancer Category/Type== [https://ccga.io/index.php/Mature_B-Cell_Neoplasms Mature B-cell neopla..."