Difference between revisions of "Primary Amyloidosis"

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==Primary Author(s)*==
 
==Primary Author(s)*==
  
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Heather E. Williams, PhD, MS, PgD, ErCLG
  
 
__TOC__
 
__TOC__
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*These monoclonal Ig deposition diseases overlap as clinically similar conditions—but likely represent chemically distinctive manifestations of similar pathological processes, which can be placed into two major categories: 1) primary amyloidosis (detailed herein); 2) [[Light Chain and Heavy Chain Deposition Disease|light chain and heavy chain deposition diseases]]<ref name=":0" /><ref name=":1">{{Cite journal|last=Ra|first=Kyle|last2=A|first2=Linos|last3=Cm|first3=Beard|last4=Rp|first4=Linke|last5=Ma|first5=Gertz|last6=Wm|first6=O'Fallon|last7=Lt|first7=Kurland|date=1992|title=Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989|url=https://pubmed.ncbi.nlm.nih.gov/1558973/|language=en|pmid=1558973}}</ref>
 
*These monoclonal Ig deposition diseases overlap as clinically similar conditions—but likely represent chemically distinctive manifestations of similar pathological processes, which can be placed into two major categories: 1) primary amyloidosis (detailed herein); 2) [[Light Chain and Heavy Chain Deposition Disease|light chain and heavy chain deposition diseases]]<ref name=":0" /><ref name=":1">{{Cite journal|last=Ra|first=Kyle|last2=A|first2=Linos|last3=Cm|first3=Beard|last4=Rp|first4=Linke|last5=Ma|first5=Gertz|last6=Wm|first6=O'Fallon|last7=Lt|first7=Kurland|date=1992|title=Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989|url=https://pubmed.ncbi.nlm.nih.gov/1558973/|language=en|pmid=1558973}}</ref>
*An acquired systemic amyloidosis, primary amyloidosis or the preferred term “AL amyloidosis,” results from a plasma cell or in rare instances, a lymphoplasmacytic neoplasm
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*An acquired systemic amyloidosis, primary amyloidosis or the preferred term “AL amyloidosis,” results from a plasma cell (pc) or in rare instances, a lymphoplasmacytic neoplasm
 
*AL amyloidosis is a rare clonal plasma cell dyscrasia, with a particularly devastating clinical phenotype that results from the extracellular amyloid fibril deposition in vital organs<ref>{{Cite journal|last=Ah|first=Bryce|last2=Rp|first2=Ketterling|last3=Ma|first3=Gertz|last4=M|first4=Lacy|last5=Ra|first5=Knudson|last6=S|first6=Zeldenrust|last7=S|first7=Kumar|last8=S|first8=Hayman|last9=F|first9=Buadi|date=2009|title=Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/19211640/|language=en|doi=10.3324/haematol.13369|pmc=PMC2649355|pmid=19211640}}</ref><ref name=":4">{{Cite journal|last=G|first=Merlini|date=2017|title=AL amyloidosis: from molecular mechanisms to targeted therapies|url=https://pubmed.ncbi.nlm.nih.gov/29222231/|language=en|doi=10.1182/asheducation-2017.1.1|pmc=PMC6142527|pmid=29222231}}</ref><ref>{{Cite journal|last=Ryšavá|first=Romana|date=2019|title=AL amyloidosis: advances in diagnostics and treatment|url=https://academic.oup.com/ndt/article/34/9/1460/5123556|journal=Nephrology Dialysis Transplantation|language=en|volume=34|issue=9|pages=1460–1466|doi=10.1093/ndt/gfy291|issn=0931-0509}}</ref>
 
*AL amyloidosis is a rare clonal plasma cell dyscrasia, with a particularly devastating clinical phenotype that results from the extracellular amyloid fibril deposition in vital organs<ref>{{Cite journal|last=Ah|first=Bryce|last2=Rp|first2=Ketterling|last3=Ma|first3=Gertz|last4=M|first4=Lacy|last5=Ra|first5=Knudson|last6=S|first6=Zeldenrust|last7=S|first7=Kumar|last8=S|first8=Hayman|last9=F|first9=Buadi|date=2009|title=Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/19211640/|language=en|doi=10.3324/haematol.13369|pmc=PMC2649355|pmid=19211640}}</ref><ref name=":4">{{Cite journal|last=G|first=Merlini|date=2017|title=AL amyloidosis: from molecular mechanisms to targeted therapies|url=https://pubmed.ncbi.nlm.nih.gov/29222231/|language=en|doi=10.1182/asheducation-2017.1.1|pmc=PMC6142527|pmid=29222231}}</ref><ref>{{Cite journal|last=Ryšavá|first=Romana|date=2019|title=AL amyloidosis: advances in diagnostics and treatment|url=https://academic.oup.com/ndt/article/34/9/1460/5123556|journal=Nephrology Dialysis Transplantation|language=en|volume=34|issue=9|pages=1460–1466|doi=10.1093/ndt/gfy291|issn=0931-0509}}</ref>
 
*The AL amyloid fibrils derive from ''N-''terminal region of monoclonal immunoglobulin light chains that consist of the whole or part of the variable (V<sub>I</sub>) domain<ref name=":2">{{Cite journal|date=2004|title=Guidelines on the diagnosis and management of AL amyloidosis|url=http://doi.wiley.com/10.1111/j.1365-2141.2004.04970.x|journal=British Journal of Haematology|language=en|volume=125|issue=6|pages=681–700|doi=10.1111/j.1365-2141.2004.04970.x|issn=0007-1048}}</ref>  
 
*The AL amyloid fibrils derive from ''N-''terminal region of monoclonal immunoglobulin light chains that consist of the whole or part of the variable (V<sub>I</sub>) domain<ref name=":2">{{Cite journal|date=2004|title=Guidelines on the diagnosis and management of AL amyloidosis|url=http://doi.wiley.com/10.1111/j.1365-2141.2004.04970.x|journal=British Journal of Haematology|language=en|volume=125|issue=6|pages=681–700|doi=10.1111/j.1365-2141.2004.04970.x|issn=0007-1048}}</ref>  
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*Immunoglobulin light chain amyloidosis (AL)
 
*Immunoglobulin light chain amyloidosis (AL)
 
*AL amyloidosis (preferred in recent literature over Primary Amyloidosis, the WHO term)
 
*AL amyloidosis (preferred in recent literature over Primary Amyloidosis, the WHO term)
 +
*AL amyloidosis (ALA)
  
 
==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
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==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
  
Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and [[Multiple Myeloma]] (MM). However, notably, the frequency of the [t(11;14)(q13;q32), ''IGH-CCND1''] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and MM.
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Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and [[Multiple Myeloma]] (MM). However, notably, the frequency of the [t(11;14)(q13;q32), ''IGH-CCND1''] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and [[Multiple Myeloma|MM]]. The [t(11;14)(q13;q32), ''IGH-CCND1''] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and [[Multiple Myeloma|MM]] (15-20%)<ref name=":0" /><ref name=":9" />. The [t(11;14)(q13;q32), ''IGH-CCND1''] fusion results from the juxtaposition of the ''CCND1'' proto-oncogene at 11q13 with the immunoglobulin heavy chain (''IGH'') locus at 14q32<ref>{{Cite journal|last=Hayman|first=Suzanne R.|last2=Bailey|first2=Richard J.|last3=Jalal|first3=Syed M.|last4=Ahmann|first4=Gregory J.|last5=Dispenzieri|first5=Angela|last6=Gertz|first6=Morie A.|last7=Greipp|first7=Philip R.|last8=Kyle|first8=Robert A.|last9=Lacy|first9=Martha Q.|date=2001|title=Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis|url=https://ashpublications.org/blood/article/98/7/2266/107138/Translocations-involving-the-immunoglobulin|journal=Blood|language=en|volume=98|issue=7|pages=2266–2268|doi=10.1182/blood.V98.7.2266|issn=1528-0020}}</ref><ref>{{Cite journal|last=Fonseca|first=Rafael|last2=Rajkumar|first2=S. Vincent|last3=Ahmann|first3=Gregory J.|last4=Jalal|first4=Syed M.|last5=Hoyer|first5=James D.|last6=Gertz|first6=Morie A.|last7=Kyle|first7=Robert A.|last8=Greipp|first8=Philip R.|last9=Dewald|first9=Gordon W.|date=2000|title=FISH Demonstrates Treatment-Related Chromosome Damage in Myeloid but not Plasma Cells in Primary Systemic Amyloidosis|url=http://www.tandfonline.com/doi/full/10.3109/10428190009065839|journal=Leukemia & Lymphoma|language=en|volume=39|issue=3-4|pages=391–395|doi=10.3109/10428190009065839|issn=1042-8194}}</ref><ref>{{Cite journal|last=Saleem|first=Mohamed|last2=Yusoff|first2=Narazah Mohd|date=2016|title=Fusion genes in malignant neoplastic disorders of haematopoietic system|url=https://www.tandfonline.com/doi/full/10.1080/10245332.2015.1106816|journal=Hematology|language=en|volume=21|issue=9|pages=501–512|doi=10.1080/10245332.2015.1106816|issn=1607-8454}}</ref>.
 
 
{| class="wikitable sortable"
 
|-
 
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
 
|-
 
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 5%
 
|-
 
|EXAMPLE t(8;21)(q22;q22)||EXAMPLE 5'RUNX1 / 3'RUNXT1||EXAMPLE der(8)||EXAMPLE 5%
 
|}
 
 
 
==Characteristic Chromosomal Aberrations / Patterns==
 
==Characteristic Chromosomal Aberrations / Patterns==
  
Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Merz|first2=Maximilian|last3=Hielscher|first3=Thomas|last4=Granzow|first4=Martin|last5=Hoffmann|first5=Korbinian|last6=Krämer|first6=Alwin|last7=Raab|first7=Marc-Steffen|last8=Hillengass|first8=Jens|last9=Seckinger|first9=Anja|date=2018|title=Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma|url=https://ashpublications.org/bloodadvances/article/2/20/2607/16105/Cytogenetic-intraclonal-heterogeneity-of-plasma|journal=Blood Advances|language=en|volume=2|issue=20|pages=2607–2618|doi=10.1182/bloodadvances.2018023200|issn=2473-9529|pmc=PMC6199662|pmid=30327369}}</ref>. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence ''in situ'' Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Stölzel|first2=Friedrich|last3=Heilig|first3=Christoph E.|last4=Kunz|first4=Christina|last5=Mohr|first5=Brigitte|last6=Jauch|first6=Anna|last7=Janssen|first7=Johannes W.G.|last8=Kramer|first8=Michael|last9=Benner|first9=Axel|date=2013|title=Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia|url=http://ascopubs.org/doi/10.1200/JCO.2013.50.7921|journal=Journal of Clinical Oncology|language=en|volume=31|issue=31|pages=3898–3905|doi=10.1200/JCO.2013.50.7921|issn=0732-183X}}</ref><ref>{{Cite journal|last=Gw|first=Dewald|last2=Ra|first2=Kyle|last3=Ga|first3=Hicks|last4=Pr|first4=Greipp|date=1985|title=The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/3926026/|language=en|pmid=3926026}}</ref>.
+
Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations<ref name=":9">{{Cite journal|last=Bochtler|first=Tilmann|last2=Merz|first2=Maximilian|last3=Hielscher|first3=Thomas|last4=Granzow|first4=Martin|last5=Hoffmann|first5=Korbinian|last6=Krämer|first6=Alwin|last7=Raab|first7=Marc-Steffen|last8=Hillengass|first8=Jens|last9=Seckinger|first9=Anja|date=2018|title=Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma|url=https://ashpublications.org/bloodadvances/article/2/20/2607/16105/Cytogenetic-intraclonal-heterogeneity-of-plasma|journal=Blood Advances|language=en|volume=2|issue=20|pages=2607–2618|doi=10.1182/bloodadvances.2018023200|issn=2473-9529|pmc=PMC6199662|pmid=30327369}}</ref>. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence ''in situ'' Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Stölzel|first2=Friedrich|last3=Heilig|first3=Christoph E.|last4=Kunz|first4=Christina|last5=Mohr|first5=Brigitte|last6=Jauch|first6=Anna|last7=Janssen|first7=Johannes W.G.|last8=Kramer|first8=Michael|last9=Benner|first9=Axel|date=2013|title=Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia|url=http://ascopubs.org/doi/10.1200/JCO.2013.50.7921|journal=Journal of Clinical Oncology|language=en|volume=31|issue=31|pages=3898–3905|doi=10.1200/JCO.2013.50.7921|issn=0732-183X}}</ref><ref>{{Cite journal|last=Gw|first=Dewald|last2=Ra|first2=Kyle|last3=Ga|first3=Hicks|last4=Pr|first4=Greipp|date=1985|title=The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/3926026/|language=en|pmid=3926026}}</ref>. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with [[Multiple Myeloma|MM]] specific probe sets or panels. These panels vary, but may include enumeration of ''CKS1B'' (1q21), ''CDKN2C'' (1p32), D9Z1/D15Z4 (CEN9, CEN15), ''RB1'' (13q14), ''TP53'' (17p13), and break-apart probes for ''MYC'' (8q24.1) or ''IGH'' (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common ''IGH'' partners: [t(4;14)(p16.3;q32); ''IGH-FGFR3''], [t(6;14)(p21;q32); ''IGH-CCND3''], [t(11;14)(q13;q32); ''IGH-CCND1''], [t(14;16)(q32;q23); ''IGH-MAF''], [t(14;20)(q32;q12); ''IGH-MAFB'']. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), ''CCND1-IGH'' aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes<ref name=":10">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Cremer|first3=Friedrich W.|last4=Heiss|first4=Christiane|last5=Benner|first5=Axel|last6=Hose|first6=Dirk|last7=Moos|first7=Marion|last8=Bila|first8=Jelena|last9=Bartram|first9=Claus R.|date=2008|title=Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability|url=https://ashpublications.org/blood/article/111/9/4700/24510/Evaluation-of-the-cytogenetic-aberration-pattern|journal=Blood|language=en|volume=111|issue=9|pages=4700–4705|doi=10.1182/blood-2007-11-122101|issn=0006-4971}}</ref><ref name=":11">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Heiss|first3=Christiane|last4=Benner|first4=Axel|last5=Moos|first5=Marion|last6=Seckinger|first6=Anja|last7=Pschowski-Zuck|first7=Stephanie|last8=Kirn|first8=Désirée|last9=Neben|first9=Kai|date=2011|title=Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)|url=https://ashpublications.org/blood/article/117/14/3809/20514/Hyperdiploidy-is-less-frequent-in-AL-amyloidosis|journal=Blood|language=en|volume=117|issue=14|pages=3809–3815|doi=10.1182/blood-2010-02-268987|issn=0006-4971}}</ref><ref>{{Cite journal|last=Cj|first=Harrison|last2=H|first2=Mazzullo|last3=Fm|first3=Ross|last4=Kl|first4=Cheung|last5=G|first5=Gerrard|last6=L|first6=Harewood|last7=A|first7=Mehta|last8=Hj|first8=Lachmann|last9=Pn|first9=Hawkins|date=2002|title=Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/11972529/|language=en|pmid=11972529}}</ref><ref>{{Cite journal|last=Kobayashi|first=Hiroki|last2=Abe|first2=Yoshiaki|last3=Miura|first3=Daisuke|last4=Narita|first4=Kentaro|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Matsue|first7=Kosei|date=2019|title=Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma|url=https://academic.oup.com/jjco/article/49/2/195/5272727|journal=Japanese Journal of Clinical Oncology|language=en|volume=49|issue=2|pages=195–198|doi=10.1093/jjco/hyy202|issn=1465-3621}}</ref>. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis<ref name=":10" /><ref name=":11" /><ref name=":12">{{Cite journal|last=Granzow|first=Martin|last2=Hegenbart|first2=Ute|last3=Hinderhofer|first3=Katrin|last4=Hose|first4=Dirk|last5=Seckinger|first5=Anja|last6=Bochtler|first6=Tilmann|last7=Hemminki|first7=Kari|last8=Goldschmidt|first8=Hartmut|last9=Schönland|first9=Stefan O.|date=2017|title=Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2016.160721|journal=Haematologica|language=en|volume=102|issue=7|pages=1281–1290|doi=10.3324/haematol.2016.160721|issn=0390-6078|pmc=PMC5566044|pmid=28341732}}</ref>. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(''v'';14) ''IGH-v'' translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and [[Multiple Myeloma|MM]] often carry gain of ''CKS1B'' (1q21), and deletions of 8p21 (''PNOC''), ''RB1'' (13q14), and ''TP53'' (17p13)<ref name=":9" />. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia<ref name=":9" />. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported<ref name=":4" /><ref>{{Cite journal|last=Muchtar|first=E|last2=Dispenzieri|first2=A|last3=Kumar|first3=S K|last4=Ketterling|first4=R P|last5=Dingli|first5=D|last6=Lacy|first6=M Q|last7=Buadi|first7=F K|last8=Hayman|first8=S R|last9=Kapoor|first9=P|date=2017|title=Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category|url=http://www.nature.com/articles/leu2016369|journal=Leukemia|language=en|volume=31|issue=7|pages=1562–1569|doi=10.1038/leu.2016.369|issn=0887-6924}}</ref>.
  
 
==Genomic Gain/Loss/LOH==
 
==Genomic Gain/Loss/LOH==
  
Put your text here and/or fill in the table
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Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see [[Characteristic chromosomal aberrations /Patterns]])<ref name=":12" />. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in [[Multiple Myeloma|MM]]; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q<ref name=":13">{{Cite journal|last=Paiva|first=Bruno|last2=Martinez-Lopez|first2=Joaquin|last3=Corchete|first3=Luis A.|last4=Sanchez-Vega|first4=Beatriz|last5=Rapado|first5=Inmaculada|last6=Puig|first6=Noemi|last7=Barrio|first7=Santiago|last8=Sanchez|first8=Maria-Luz|last9=Alignani|first9=Diego|date=2016|title=Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis|url=https://ashpublications.org/blood/article/127/24/3035/35439/Phenotypic-transcriptomic-and-genomic-features-of|journal=Blood|language=en|volume=127|issue=24|pages=3035–3039|doi=10.1182/blood-2015-10-673095|issn=0006-4971}}</ref>. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)<ref name=":12" />. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort<ref name=":12" />. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(''v'';14) ''IGH-''unknown partner<ref name=":12" /><ref>{{Cite journal|last=Cremer|first=Friedrich W.|last2=Bila|first2=Jelena|last3=Buck|first3=Isabelle|last4=Kartal|first4=Mutlu|last5=Hose|first5=Dirk|last6=Ittrich|first6=Carina|last7=Benner|first7=Axel|last8=Raab|first8=Marc S.|last9=Theil|first9=Ann-Cathrin|date=2005|title=Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics|url=http://doi.wiley.com/10.1002/gcc.20231|journal=Genes, Chromosomes and Cancer|language=en|volume=44|issue=2|pages=194–203|doi=10.1002/gcc.20231|issn=1045-2257}}</ref>. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis<ref name=":13" />. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see [[Gene mutations (SNV/INVDEL)]]<ref>{{Cite journal|last=Huang|first=Xu-Fei|last2=Jian|first2=Sun|last3=Lu|first3=Jun-Liang|last4=Shen|first4=Kai-Ni|last5=Feng|first5=Jun|last6=Zhang|first6=Cong-Li|last7=Tian|first7=Zhuang|last8=Wang|first8=Jia-Li|last9=Lei|first9=Wan-Jun|date=2020|title=Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1678464|journal=Amyloid|language=en|volume=27|issue=1|pages=36–44|doi=10.1080/13506129.2019.1678464|issn=1350-6129}}</ref>.
 
 
{| class="wikitable sortable"
 
|-
 
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
 
|-
 
|EXAMPLE 8||EXAMPLE Gain||EXAMPLE chr8:0-1000000
 
|-
 
|EXAMPLE 7||EXAMPLE Loss||EXAMPLE chr7:0-1000000
 
|}
 
 
 
==Gene Mutations (SNV/INDEL)==
 
==Gene Mutations (SNV/INDEL)==
  
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==References==
 
==References==
(use "Cite" icon at top of page)
 
 
<references />
 
<references />
  
 
==Notes==
 
==Notes==
 
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<nowiki>*</nowiki>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.

Revision as of 02:06, 29 July 2020

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Primary Author(s)*

Heather E. Williams, PhD, MS, PgD, ErCLG

Cancer Category/Type

Mature B-cell neoplasms

Cancer Sub-Classification / Subtype

Monoclonal immunoglobulin deposition disease

Definition / Description of Disease

  • A member of the group of “monoclonal immunoglobulin deposition diseases” that are characterized by visceral and soft tissue deposition of aberrant immunoglobulin (Ig), which subsequently results in organ dysfunction[1][2][3][4][5][6][7][8][9]
  • These monoclonal Ig deposition diseases overlap as clinically similar conditions—but likely represent chemically distinctive manifestations of similar pathological processes, which can be placed into two major categories: 1) primary amyloidosis (detailed herein); 2) light chain and heavy chain deposition diseases[9][10]
  • An acquired systemic amyloidosis, primary amyloidosis or the preferred term “AL amyloidosis,” results from a plasma cell (pc) or in rare instances, a lymphoplasmacytic neoplasm
  • AL amyloidosis is a rare clonal plasma cell dyscrasia, with a particularly devastating clinical phenotype that results from the extracellular amyloid fibril deposition in vital organs[11][12][13]
  • The AL amyloid fibrils derive from N-terminal region of monoclonal immunoglobulin light chains that consist of the whole or part of the variable (VI) domain[14]
    • The structure and unique nature of all monoclonal light chains influences their inherent propensity (for some) to form amyloid fibrils[14]
    • The amyloid formed from monoclonal light chains can exist in a partly unfolded state, which involves loss of tertiary or higher order structures[14]. Amyloids will readily aggregate in the ß-sheet structure to create protofilaments and fibril; this process is progressive as a ‘seeding” event serves as a template that facilities further amyloid deposition, which allows expansion of deposition by capturing further precursor molecules[14]

Synonyms / Terminology

  • Immunoglobulin light chain amyloidosis (AL)
  • AL amyloidosis (preferred in recent literature over Primary Amyloidosis, the WHO term)
  • AL amyloidosis (ALA)

Epidemiology / Prevalence

  • AL amyloidosis is an uncommon disorder and its exact incidence is unknown[15]
  • Within the US, the incidence is estimated at 9-14 cases per million person years, but the true prevalence may be higher due to under diagnosis[10][16][17]
  • Considered a disease of the elderly, the incidence of AL amyloidosis increases with age[10][16]
    • A small proportion of patients (~1.3%) are diagnosed under the age of 34, with the median age at diagnosis of 63 years of age[18]
  • There is a male predominance, with men reported in recent studies to account for 55-70% of patients[5][18][19]
  • There is limited data regarding AL amyloidosis incidence across ethnic populations, however, the disease is known to occur in all races and geographical regions[9]

Clinical Features

  • The signs and symptoms that raise the clinical suspicion for a possible diagnosis of amyloidosis are generally nonspecific; therefore, the establishment of an AL amyloidosis is difficult and is highly reliant upon a clinical suspicion[17]
  • Clinical presentations vary, ranging from more rapidly progressive symptoms to slowly evolving or a paucity of symptoms among others[16]
  • Nearly 25% of patients are diagnosed late, and many present with advanced, irreversible cardiac damage, and often succumb to within 12 months of the diagnosis[12]
  • Clinical presentations generally relate and are of a consequence of amyloid in organs and tissues, and it is often the presentation of symptoms within a particular organ that predominate, which initiates the diagnosis[12][17]
  • Signs of the disease in the early stages include peripheral neuropathy (~15-20%), carpal tunnel syndrome (~21%), and bone pain (~5%)[9]. Other major symptoms, in addition to the extremely common presenting symptoms of fatigue and weight loss, relate to congestive heart failure (~15-20%), nephrotic syndrome (~28%), or malabsorption (~5%) are common[5][9]
  • Physical observations include hepatomegaly (~25-30%), macroglossia (~10%), and purpura, commonly of periorbital or facial presentation (~15%)[5]
  • Individuals with congestive heart failure or nephrotic syndrome often present with edema[5]
  • Few patients present with splenomegaly, lymphadenopathy, skin and soft tissue thickening, a hoarse voice (due to vocal cord infiltration), hypoadrenalism or hypothyroidism (due to deposits within the adrenal or thyroid glands, respectively)[20]
  • Overlooking the diagnosis of AL amyloidosis leads to therapy delay, and is a relatively common event, and it represents an error of diagnostic consideration which has resulted in an unsatisfactory survival for patients[15]

Sites of Involvement

  • The accumulation of amyloid light chain progressively disrupts numerous tissues and organs, e.g. subcutaneous fat, kidneys, heart, liver, gastrointestinal tracts, peripheral nervous system, and bone marrow, ultimately leading to organ failure[9]
  • The deposition of amyloid does not evoke (or of little) reaction locally within the tissues, and there is poor correlation between the level of amyloid depositions and the degree of impairment to organ function[14]
  • The morbidity and mortality in AL amyloidosis results from the effects of the toxic monoclonal protein, and impact to cardiac function is a critical determinate of survival[21][22]
  • AL amyloidosis is a progressive and fatal disease, with significant mortality within one year of diagnosis[12][23]

Morphologic Features

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Immunophenotype

Put your text here and/or fill in the table

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

Chromosomal Rearrangements (Gene Fusions)

Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and Multiple Myeloma (MM). However, notably, the frequency of the [t(11;14)(q13;q32), IGH-CCND1] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and MM. The [t(11;14)(q13;q32), IGH-CCND1] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and MM (15-20%)[9][24]. The [t(11;14)(q13;q32), IGH-CCND1] fusion results from the juxtaposition of the CCND1 proto-oncogene at 11q13 with the immunoglobulin heavy chain (IGH) locus at 14q32[25][26][27].

Characteristic Chromosomal Aberrations / Patterns

Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations[24]. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence in situ Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases[28][29]. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with MM specific probe sets or panels. These panels vary, but may include enumeration of CKS1B (1q21), CDKN2C (1p32), D9Z1/D15Z4 (CEN9, CEN15), RB1 (13q14), TP53 (17p13), and break-apart probes for MYC (8q24.1) or IGH (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common IGH partners: [t(4;14)(p16.3;q32); IGH-FGFR3], [t(6;14)(p21;q32); IGH-CCND3], [t(11;14)(q13;q32); IGH-CCND1], [t(14;16)(q32;q23); IGH-MAF], [t(14;20)(q32;q12); IGH-MAFB]. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), CCND1-IGH aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes[30][31][32][33]. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis[30][31][34]. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(v;14) IGH-v translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and MM often carry gain of CKS1B (1q21), and deletions of 8p21 (PNOC), RB1 (13q14), and TP53 (17p13)[24]. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia[24]. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported[12][35].

Genomic Gain/Loss/LOH

Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see Characteristic chromosomal aberrations /Patterns)[34]. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in MM; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q[36]. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)[34]. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort[34]. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(v;14) IGH-unknown partner[34][37]. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis[36]. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see Gene mutations (SNV/INVDEL)[38].

Gene Mutations (SNV/INDEL)

Put your text here and/or fill in the tables

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53 EXAMPLE R273H EXAMPLE Tumor Suppressor EXAMPLE LOF EXAMPLE 20%

Other Mutations

Type Gene/Region/Other
Concomitant Mutations EXAMPLE IDH1 R123H
Secondary Mutations EXAMPLE Trisomy 7
Mutually Exclusive EXAMPLE EGFR Amplification

Epigenomics (Methylation)

Put your text here

Genes and Main Pathways Involved

Put your text here

Diagnostic Testing Methods

Put your text here

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Put your text here

Familial Forms

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Other Information

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Links

Monoclonal Immunoglobulin Deposition Diseases

Put your links here (use "Link" icon at top of page)

References

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  2. J, Buxbaum (1992). "Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease". PMID 1582976.
  3. Herzenberg, Andrew M.; et al. (1996). "Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case". American Journal of Kidney Diseases. 28 (1): 128–131. doi:10.1016/S0272-6386(96)90141-9.
  4. Kambham, Neeraja; et al. (1999). "Heavy chain deposition disease: The disease spectrum". American Journal of Kidney Diseases. 33 (5): 954–962. doi:10.1016/S0272-6386(99)70432-4.
  5. 5.0 5.1 5.2 5.3 5.4 Ra, Kyle; et al. (1995). "Primary systemic amyloidosis: clinical and laboratory features in 474 cases". PMID 7878478.
  6. Preud'homme, Jean-Louis; et al. (1994). "Monoclonal immunoglobulin deposition disease (Randall type). Relationship with structural abnormalities of immunoglobulin chains". Kidney International. 46 (4): 965–972. doi:10.1038/ki.1994.355.
  7. Preud'Homme, Jean-Louis; et al. (1994). "Monoclonal immunoglobulin deposition disease: A review of immunoglobulin chain alterations". International Journal of Immunopharmacology. 16 (5–6): 425–431. doi:10.1016/0192-0561(94)90032-9.
  8. Serpell, L. C.; et al. (1997). "The molecular basis of amyloidosis". Cellular and Molecular Life Sciences. 53 (12): 871. doi:10.1007/s000180050107.
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  22. Kumar, Shaji; et al. (2012). "Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements". Journal of Clinical Oncology. 30 (9): 989–995. doi:10.1200/JCO.2011.38.5724. ISSN 0732-183X. PMC 3675680. PMID 22331953.CS1 maint: PMC format (link)
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  28. Bochtler, Tilmann; et al. (2013). "Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia". Journal of Clinical Oncology. 31 (31): 3898–3905. doi:10.1200/JCO.2013.50.7921. ISSN 0732-183X.
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  32. Cj, Harrison; et al. (2002). "Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis". PMID 11972529.
  33. Kobayashi, Hiroki; et al. (2019). "Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma". Japanese Journal of Clinical Oncology. 49 (2): 195–198. doi:10.1093/jjco/hyy202. ISSN 1465-3621.
  34. 34.0 34.1 34.2 34.3 34.4 Granzow, Martin; et al. (2017). "Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis". Haematologica. 102 (7): 1281–1290. doi:10.3324/haematol.2016.160721. ISSN 0390-6078. PMC 5566044. PMID 28341732.CS1 maint: PMC format (link)
  35. Muchtar, E; et al. (2017). "Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category". Leukemia. 31 (7): 1562–1569. doi:10.1038/leu.2016.369. ISSN 0887-6924.
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  37. Cremer, Friedrich W.; et al. (2005). "Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics". Genes, Chromosomes and Cancer. 44 (2): 194–203. doi:10.1002/gcc.20231. ISSN 1045-2257.
  38. Huang, Xu-Fei; et al. (2020). "Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival". Amyloid. 27 (1): 36–44. doi:10.1080/13506129.2019.1678464. ISSN 1350-6129.

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.