HAEM5:Myelodysplastic neoplasm with biallelic TP53 inactivation: Difference between revisions
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|Subtype(s) | |Subtype(s) | ||
|Myelodysplastic neoplasm with biallelic TP53 inactivation | |Myelodysplastic neoplasm with biallelic TP53 inactivation | ||
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==Morphologic Features== | ==Morphologic Features== | ||
Morphologic dysplasia is the hallmark of MDS, including MDS-bi''TP53''; by definition, at least one lineage . ''TP53'' mutations in MDS have been associated with particularly severe granulocytic dysplasia and with increased frequency of bone marrow blasts.<ref name=":0" /><ref name=":1" /><ref>{{Cite journal|last=Della Porta|first=M. G.|last2=Travaglino|first2=E.|last3=Boveri|first3=E.|last4=Ponzoni|first4=M.|last5=Malcovati|first5=L.|last6=Papaemmanuil|first6=E.|last7=Rigolin|first7=G. M.|last8=Pascutto|first8=C.|last9=Croci|first9=G.|date=2015-01|title=Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/24935723|journal=Leukemia|volume=29|issue=1|pages=66–75|doi=10.1038/leu.2014.161|issn=1476-5551|pmid=24935723}}</ref> ''TP53'' mutations are enriched in MDS associated with bone marrow fibrosis.<ref>{{Cite journal|last=Duarte|first=Fernando B.|last2=Barbosa|first2=Maritza C.|last3=Jesus Dos Santos|first3=Talyta E.|last4=Lemes|first4=Romélia P. G.|last5=Vasconcelos|first5=João P.|last6=de Vasconcelos|first6=Paulo R. L.|last7=Rocha|first7=Francisco D.|last8=Zalcberg|first8=Ilana|last9=Coutinho|first9=Diego F.|date=2018-05|title=Bone marrow fibrosis at diagnosis is associated with TP53 overexpression and adverse prognosis in low-risk myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/28318026|journal=British Journal of Haematology|volume=181|issue=4|pages=547–549|doi=10.1111/bjh.14656|issn=1365-2141|pmid=28318026}}</ref><ref>{{Cite journal|last=Loghavi|first=Sanam|last2=Al-Ibraheemi|first2=Alyaa|last3=Zuo|first3=Zhuang|last4=Garcia-Manero|first4=Guillermo|last5=Yabe|first5=Mariko|last6=Wang|first6=Sa A.|last7=Kantarjian|first7=Hagop M.|last8=Yin|first8=Cameron C.|last9=Miranda|first9=Roberto N.|date=2015-10|title=TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis|url=https://pubmed.ncbi.nlm.nih.gov/26123119|journal=British Journal of Haematology|volume=171|issue=1|pages=91–99|doi=10.1111/bjh.13529|issn=1365-2141|pmc=5577911|pmid=26123119}}</ref> | Morphologic dysplasia is the hallmark of MDS, including MDS-bi''TP53''; by definition, at least one lineage . ''TP53'' mutations in MDS have been associated with particularly severe granulocytic dysplasia and with increased frequency of bone marrow blasts.<ref name=":0">{{Cite journal|last=Bernard|first=Elsa|last2=Nannya|first2=Yasuhito|last3=Hasserjian|first3=Robert P.|last4=Devlin|first4=Sean M.|last5=Tuechler|first5=Heinz|last6=Medina-Martinez|first6=Juan S.|last7=Yoshizato|first7=Tetsuichi|last8=Shiozawa|first8=Yusuke|last9=Saiki|first9=Ryunosuke|date=2020-10|title=Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/32747829|journal=Nature Medicine|volume=26|issue=10|pages=1549–1556|doi=10.1038/s41591-020-1008-z|issn=1546-170X|pmc=8381722|pmid=32747829}}</ref><ref name=":1">{{Cite journal|last=Haase|first=Detlef|last2=Stevenson|first2=Kristen E.|last3=Neuberg|first3=Donna|last4=Maciejewski|first4=Jaroslaw P.|last5=Nazha|first5=Aziz|last6=Sekeres|first6=Mikkael A.|last7=Ebert|first7=Benjamin L.|last8=Garcia-Manero|first8=Guillermo|last9=Haferlach|first9=Claudia|date=2019-07|title=TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups|url=https://pubmed.ncbi.nlm.nih.gov/30635634|journal=Leukemia|volume=33|issue=7|pages=1747–1758|doi=10.1038/s41375-018-0351-2|issn=1476-5551|pmc=6609480|pmid=30635634}}</ref><ref name=":4">{{Cite journal|last=Della Porta|first=M. G.|last2=Travaglino|first2=E.|last3=Boveri|first3=E.|last4=Ponzoni|first4=M.|last5=Malcovati|first5=L.|last6=Papaemmanuil|first6=E.|last7=Rigolin|first7=G. M.|last8=Pascutto|first8=C.|last9=Croci|first9=G.|date=2015-01|title=Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/24935723|journal=Leukemia|volume=29|issue=1|pages=66–75|doi=10.1038/leu.2014.161|issn=1476-5551|pmid=24935723}}</ref> ''TP53'' mutations are enriched in MDS associated with bone marrow fibrosis.<ref name=":5">{{Cite journal|last=Duarte|first=Fernando B.|last2=Barbosa|first2=Maritza C.|last3=Jesus Dos Santos|first3=Talyta E.|last4=Lemes|first4=Romélia P. G.|last5=Vasconcelos|first5=João P.|last6=de Vasconcelos|first6=Paulo R. L.|last7=Rocha|first7=Francisco D.|last8=Zalcberg|first8=Ilana|last9=Coutinho|first9=Diego F.|date=2018-05|title=Bone marrow fibrosis at diagnosis is associated with TP53 overexpression and adverse prognosis in low-risk myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/28318026|journal=British Journal of Haematology|volume=181|issue=4|pages=547–549|doi=10.1111/bjh.14656|issn=1365-2141|pmid=28318026}}</ref><ref name=":6">{{Cite journal|last=Loghavi|first=Sanam|last2=Al-Ibraheemi|first2=Alyaa|last3=Zuo|first3=Zhuang|last4=Garcia-Manero|first4=Guillermo|last5=Yabe|first5=Mariko|last6=Wang|first6=Sa A.|last7=Kantarjian|first7=Hagop M.|last8=Yin|first8=Cameron C.|last9=Miranda|first9=Roberto N.|date=2015-10|title=TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis|url=https://pubmed.ncbi.nlm.nih.gov/26123119|journal=British Journal of Haematology|volume=171|issue=1|pages=91–99|doi=10.1111/bjh.13529|issn=1365-2141|pmc=5577911|pmid=26123119}}</ref> | ||
[[File:Dysplastic_blood_and_bone_marrow_features_in_MDS.tif|alt=|thumb|1300x1300px|Multilineage dysplasia in MDS. Left: ''TP53'' mutation is associated with severe dysgranulopoiesis, including hypogranular and hypolobated neutrophils (black arrows). Center: Dysgranulopoiesis (arrows) and dyserythropoiesis with basophilic stippling and nuclear atypia (arrowheads). Right: Dysmegakaryopoiesis with separated nuclear lobes and small hypolobated cells (white arrows). Image from: Eric McGinnis, Vancouver General Hospital|none]] | [[File:Dysplastic_blood_and_bone_marrow_features_in_MDS.tif|alt=|thumb|1300x1300px|Multilineage dysplasia in MDS. Left: ''TP53'' mutation is associated with severe dysgranulopoiesis, including hypogranular and hypolobated neutrophils (black arrows). Center: Dysgranulopoiesis (arrows) and dyserythropoiesis with basophilic stippling and nuclear atypia (arrowheads). Right: Dysmegakaryopoiesis with separated nuclear lobes and small hypolobated cells (white arrows). Image from: Eric McGinnis, Vancouver General Hospital|none]] | ||
<br />[[File:Bone marrow morphology in MDS biTP53.tif|thumb|1300x1300px|MDS-bi''TP53'' is associated with high-grade features, including increased blasts and bone marrow fibrosis, at an increased frequency. Left: Bone marrow showing disorganized hematopoiesis and increased numbers of blasts forming small clusters (white arrows). Center: Immunohistochemical staining for CD34 highlighting blasts in increased number and small dense blast clusters (arrowheads). Right: Bone marrow reticulin fibrosis (black arrows). Image from: Eric McGinnis, Vancouver General Hospital|alt=|none]] | <br />[[File:Bone marrow morphology in MDS biTP53.tif|thumb|1300x1300px|MDS-bi''TP53'' is associated with high-grade features, including increased blasts and bone marrow fibrosis, at an increased frequency. Left: Bone marrow showing disorganized hematopoiesis and increased numbers of blasts forming small clusters (white arrows). Center: Immunohistochemical staining for CD34 highlighting blasts in increased number and small dense blast clusters (arrowheads). Right: Bone marrow reticulin fibrosis (black arrows). Image from: Eric McGinnis, Vancouver General Hospital|alt=|none]] | ||
<br /> | <br /> | ||
==Immunophenotype== | ==Immunophenotype== | ||
Immunophenotyping by flow cytometry using assays designed to detect abnormal numbers, light scatter characteristics, and antigen expression patterns of hematopoietic cells can provide useful data supportive of a diagnosis of MDS (and aid in blast enumeration); however, these findings are not specific to MDS-bi''TP53'' and are not formalized in current diagnostic criteria.<ref name=":2" /><ref>{{Cite journal|last=Kern|first=Wolfgang|last2=Westers|first2=Theresia M.|last3=Bellos|first3=Frauke|last4=Bene|first4=Marie Christine|last5=Bettelheim|first5=Peter|last6=Brodersen|first6=Lisa Eidenschink|last7=Burbury|first7=Kate|last8=Chu|first8=Sung-Chao|last9=Cullen|first9=Matthew|date=2023-01|title=Multicenter prospective evaluation of diagnostic potential of flow cytometric aberrancies in myelodysplastic syndromes by the ELN iMDS flow working group|url=https://pubmed.ncbi.nlm.nih.gov/36416672|journal=Cytometry. Part B, Clinical Cytometry|volume=104|issue=1|pages=51–65|doi=10.1002/cyto.b.22105|issn=1552-4957|pmid=36416672}}</ref> | Immunophenotyping by flow cytometry using assays designed to detect abnormal numbers, light scatter characteristics, and antigen expression patterns of hematopoietic cells can provide useful data supportive of a diagnosis of MDS (and aid in blast enumeration); however, these findings are not specific to MDS-bi''TP53'' and are not formalized in current diagnostic criteria.<ref name=":2">Germing U., Claudi M., Zerbini N., et al. Myelodysplastic neoplasm with biallelic TP53 inactivation. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022 [cited YYYY Mmm D]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: <nowiki>https://tumourclassification.iarc.who.int/chapters/63</nowiki>.</ref><ref name=":7">{{Cite journal|last=Kern|first=Wolfgang|last2=Westers|first2=Theresia M.|last3=Bellos|first3=Frauke|last4=Bene|first4=Marie Christine|last5=Bettelheim|first5=Peter|last6=Brodersen|first6=Lisa Eidenschink|last7=Burbury|first7=Kate|last8=Chu|first8=Sung-Chao|last9=Cullen|first9=Matthew|date=2023-01|title=Multicenter prospective evaluation of diagnostic potential of flow cytometric aberrancies in myelodysplastic syndromes by the ELN iMDS flow working group|url=https://pubmed.ncbi.nlm.nih.gov/36416672|journal=Cytometry. Part B, Clinical Cytometry|volume=104|issue=1|pages=51–65|doi=10.1002/cyto.b.22105|issn=1552-4957|pmid=36416672}}</ref> | ||
Immunohistochemical evaluation of TP53 protein expression in bone marrow specimens can be used to inform ''TP53'' mutation status. Several studies evaluating TP53 protein expression in bone marrow specimens have consistently demonstrated nuclear overexpression (thought to result from stabilization of TP53 resulting from dominant negative mutations), when present in an increased fraction of cells, to be associated with pathogenic ''TP53'' mutation and to be similarly predictive of poor outcomes.<ref name=":3">{{Cite journal|last=Tashakori|first=Mehrnoosh|last2=Kadia|first2=Tapan|last3=Loghavi|first3=Sanam|last4=Daver|first4=Naval|last5=Kanagal-Shamanna|first5=Rashmi|last6=Pierce|first6=Sherry|last7=Sui|first7=Dawen|last8=Wei|first8=Peng|last9=Khodakarami|first9=Farnoosh|date=2022-07-07|title=TP53 copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/35390143|journal=Blood|volume=140|issue=1|pages=58–72|doi=10.1182/blood.2021013983|issn=1528-0020|pmc=9346958|pmid=35390143}}</ref><ref>{{Cite journal|last=Saft|first=Leonie|last2=Karimi|first2=Mohsen|last3=Ghaderi|first3=Mehran|last4=Matolcsy|first4=András|last5=Mufti|first5=Ghulam J.|last6=Kulasekararaj|first6=Austin|last7=Göhring|first7=Gudrun|last8=Giagounidis|first8=Aristoteles|last9=Selleslag|first9=Dominik|date=2014-06|title=p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)|url=https://pubmed.ncbi.nlm.nih.gov/24682512|journal=Haematologica|volume=99|issue=6|pages=1041–1049|doi=10.3324/haematol.2013.098103|issn=1592-8721|pmc=4040908|pmid=24682512}}</ref><ref>{{Cite journal|last=Loghavi|first=Sanam|last2=Al-Ibraheemi|first2=Alyaa|last3=Zuo|first3=Zhuang|last4=Garcia-Manero|first4=Guillermo|last5=Yabe|first5=Mariko|last6=Wang|first6=Sa A.|last7=Kantarjian|first7=Hagop M.|last8=Yin|first8=Cameron C.|last9=Miranda|first9=Roberto N.|date=2015-10|title=TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis|url=https://pubmed.ncbi.nlm.nih.gov/26123119|journal=British Journal of Haematology|volume=171|issue=1|pages=91–99|doi=10.1111/bjh.13529|issn=1365-2141|pmc=5577911|pmid=26123119}}</ref><ref>{{Cite journal|last=Ruzinova|first=Marianna B.|last2=Lee|first2=Yi-Shan|last3=Duncavage|first3=Eric J.|last4=Welch|first4=John S.|date=2019-08|title=TP53 immunohistochemistry correlates with TP53 mutation status and clearance in decitabine-treated patients with myeloid malignancies|url=https://pubmed.ncbi.nlm.nih.gov/30792212|journal=Haematologica|volume=104|issue=8|pages=e345–e348|doi=10.3324/haematol.2018.205302|issn=1592-8721|pmc=6669137|pmid=30792212}}</ref><ref>{{Cite journal|last=Kubbutat|first=M. H.|last2=Jones|first2=S. N.|last3=Vousden|first3=K. H.|date=1997-05-15|title=Regulation of p53 stability by Mdm2|url=https://pubmed.ncbi.nlm.nih.gov/9153396|journal=Nature|volume=387|issue=6630|pages=299–303|doi=10.1038/387299a0|issn=0028-0836|pmid=9153396}}</ref> Complete absence of TP53 expression demonstrable by immunohistochemistry has similarly been associated with ''TP53'' mutation (typically frameshift, nonsense, and splice site, often with coexisting copy loss).<ref name=":3" /> | Immunohistochemical evaluation of TP53 protein expression in bone marrow specimens can be used to inform ''TP53'' mutation status. Several studies evaluating TP53 protein expression in bone marrow specimens have consistently demonstrated nuclear overexpression (thought to result from stabilization of TP53 resulting from dominant negative mutations), when present in an increased fraction of cells, to be associated with pathogenic ''TP53'' mutation and to be similarly predictive of poor outcomes.<ref name=":3">{{Cite journal|last=Tashakori|first=Mehrnoosh|last2=Kadia|first2=Tapan|last3=Loghavi|first3=Sanam|last4=Daver|first4=Naval|last5=Kanagal-Shamanna|first5=Rashmi|last6=Pierce|first6=Sherry|last7=Sui|first7=Dawen|last8=Wei|first8=Peng|last9=Khodakarami|first9=Farnoosh|date=2022-07-07|title=TP53 copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/35390143|journal=Blood|volume=140|issue=1|pages=58–72|doi=10.1182/blood.2021013983|issn=1528-0020|pmc=9346958|pmid=35390143}}</ref><ref name=":8">{{Cite journal|last=Saft|first=Leonie|last2=Karimi|first2=Mohsen|last3=Ghaderi|first3=Mehran|last4=Matolcsy|first4=András|last5=Mufti|first5=Ghulam J.|last6=Kulasekararaj|first6=Austin|last7=Göhring|first7=Gudrun|last8=Giagounidis|first8=Aristoteles|last9=Selleslag|first9=Dominik|date=2014-06|title=p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)|url=https://pubmed.ncbi.nlm.nih.gov/24682512|journal=Haematologica|volume=99|issue=6|pages=1041–1049|doi=10.3324/haematol.2013.098103|issn=1592-8721|pmc=4040908|pmid=24682512}}</ref><ref name=":9">{{Cite journal|last=Loghavi|first=Sanam|last2=Al-Ibraheemi|first2=Alyaa|last3=Zuo|first3=Zhuang|last4=Garcia-Manero|first4=Guillermo|last5=Yabe|first5=Mariko|last6=Wang|first6=Sa A.|last7=Kantarjian|first7=Hagop M.|last8=Yin|first8=Cameron C.|last9=Miranda|first9=Roberto N.|date=2015-10|title=TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis|url=https://pubmed.ncbi.nlm.nih.gov/26123119|journal=British Journal of Haematology|volume=171|issue=1|pages=91–99|doi=10.1111/bjh.13529|issn=1365-2141|pmc=5577911|pmid=26123119}}</ref><ref name=":10">{{Cite journal|last=Ruzinova|first=Marianna B.|last2=Lee|first2=Yi-Shan|last3=Duncavage|first3=Eric J.|last4=Welch|first4=John S.|date=2019-08|title=TP53 immunohistochemistry correlates with TP53 mutation status and clearance in decitabine-treated patients with myeloid malignancies|url=https://pubmed.ncbi.nlm.nih.gov/30792212|journal=Haematologica|volume=104|issue=8|pages=e345–e348|doi=10.3324/haematol.2018.205302|issn=1592-8721|pmc=6669137|pmid=30792212}}</ref><ref name=":11">{{Cite journal|last=Kubbutat|first=M. H.|last2=Jones|first2=S. N.|last3=Vousden|first3=K. H.|date=1997-05-15|title=Regulation of p53 stability by Mdm2|url=https://pubmed.ncbi.nlm.nih.gov/9153396|journal=Nature|volume=387|issue=6630|pages=299–303|doi=10.1038/387299a0|issn=0028-0836|pmid=9153396}}</ref> Complete absence of TP53 expression demonstrable by immunohistochemistry has similarly been associated with ''TP53'' mutation (typically frameshift, nonsense, and splice site, often with coexisting copy loss).<ref name=":3" /> | ||
<br /> | <br /> | ||
[[File:TP53 IHC panel.tif|thumb|1300x1300px|Immunohistochemical evaluation of TP53 expression correlates with ''TP53'' mutation status in MDS-bi''TP53''. Left: Normal TP53 expression in MDS without ''TP53'' mutation; cells show variable nuclear staining. Center: TP53 overexpression in MDS with biallelic ''TP53'' inactivation resulting from a missense mutation and loss of 17p; the majority of cells show excessive nuclear staining. Right: Absence of TP53 expression in MDS with biallelic ''TP53'' inactivation resulting from a truncating mutation and loss of 17p; the great majority of cells show absence of any detectable TP53 staining.|alt=|none]] | [[File:TP53 IHC panel.tif|thumb|1300x1300px|Immunohistochemical evaluation of TP53 expression correlates with ''TP53'' mutation status in MDS-bi''TP53''. Left: Normal TP53 expression in MDS without ''TP53'' mutation; cells show variable nuclear staining. Center: TP53 overexpression in MDS with biallelic ''TP53'' inactivation resulting from a missense mutation and loss of 17p; the majority of cells show excessive nuclear staining. Right: Absence of TP53 expression in MDS with biallelic ''TP53'' inactivation resulting from a truncating mutation and loss of 17p; the great majority of cells show absence of any detectable TP53 staining.|alt=|none]] | ||
==WHO Essential and Desirable Genetic Diagnostic Criteria== | ==WHO Essential and Desirable Genetic Diagnostic Criteria== | ||
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span> | <span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span> | ||
| Line 551: | Line 451: | ||
*A complex karyotype (at least three distinct abnormalities excluding loss of Y) and/or 17p deletion detected by analysis of banded chromosomes, in the context of one detected ''TP53'' variant, can be considered evidence of biallelic inactivation | *A complex karyotype (at least three distinct abnormalities excluding loss of Y) and/or 17p deletion detected by analysis of banded chromosomes, in the context of one detected ''TP53'' variant, can be considered evidence of biallelic inactivation | ||
*If myeloid blasts account for 10-19% of cellularity in blood or bone marrow then a diagnosis of MDS/AML with mutated ''TP53'' is applied (for which only a single ''TP53'' mutation with VAF ≥10% is required for diagnosis) | *If myeloid blasts account for 10-19% of cellularity in blood or bone marrow then a diagnosis of MDS/AML with mutated ''TP53'' is applied (for which only a single ''TP53'' mutation with VAF ≥10% is required for diagnosis) | ||
This disease is <u>defined/characterized</u> as detailed below: | |||
* Myelodysplastic neoplasm with biallelic ''TP53'' inactivation (MDS-bi''TP53'') is a myeloid neoplasm which is characterized by ineffective hematopoiesis, manifesting clinically and pathologically as cytopenia(s), bone marrow morphologic dysplasia, and propensity to progress to acute myeloid leukemia, and which carries either two ''TP53'' mutations or a single mutation accompanied by either evidence of concurrent ''TP53'' deletion or copy-neutral loss of heterozygosity (LOH); in the appropriate setting, a pathogenic ''TP53'' variant with high variant allele fraction (VAF > 49%) can be considered presumptive evidence of biallelic inactivation status.<ref>{{Cite journal|last=Khoury|first=Joseph D.|last2=Solary|first2=Eric|last3=Abla|first3=Oussama|last4=Akkari|first4=Yassmine|last5=Alaggio|first5=Rita|last6=Apperley|first6=Jane F.|last7=Bejar|first7=Rafael|last8=Berti|first8=Emilio|last9=Busque|first9=Lambert|date=2022-07|title=The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/35732831|journal=Leukemia|volume=36|issue=7|pages=1703–1719|doi=10.1038/s41375-022-01613-1|issn=1476-5551|pmc=9252913|pmid=35732831}}</ref><ref name=":2" /> | |||
* MDS bi-''TP53'' supersedes other genetically and morphologically defined MDS entities. By definition, in addition to the requirement for evidence of biallelic ''TP53'' inactivation, general criteria for diagnosis of MDS must be met and diagnostic criteria for acute myeloid leukemia must not be met. Acute erythroid leukemia, in which ''TP53'' mutations are common, must be specifically excluded by morphologic and/or immunophenotypic assessment.<ref name=":2" /> | |||
The <u>epidemiology/prevalence</u> of this disease is detailed below: | |||
* Myelodysplastic neoplasm with biallelic ''TP53'' inactivation (MDS-bi''TP53'') is a myeloid neoplasm which is characterized by ineffective hematopoiesis, manifesting clinically and pathologically as cytopenia(s), bone marrow morphologic dysplasia, and propensity to progress to acute myeloid leukemia, and which carries either two ''TP53'' mutations or a single mutation accompanied by either evidence of concurrent ''TP53'' deletion or copy-neutral loss of heterozygosity (LOH); in the appropriate setting, a pathogenic ''TP53'' variant with high variant allele fraction (VAF > 49%) can be considered presumptive evidence of biallelic inactivation status.<ref>{{Cite journal|last=Khoury|first=Joseph D.|last2=Solary|first2=Eric|last3=Abla|first3=Oussama|last4=Akkari|first4=Yassmine|last5=Alaggio|first5=Rita|last6=Apperley|first6=Jane F.|last7=Bejar|first7=Rafael|last8=Berti|first8=Emilio|last9=Busque|first9=Lambert|date=2022-07|title=The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/35732831|journal=Leukemia|volume=36|issue=7|pages=1703–1719|doi=10.1038/s41375-022-01613-1|issn=1476-5551|pmc=9252913|pmid=35732831}}</ref><ref name=":22">Germing U., Claudi M., Zerbini N., et al. Myelodysplastic neoplasm with biallelic TP53 inactivation. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022 [cited YYYY Mmm D]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: <nowiki>https://tumourclassification.iarc.who.int/chapters/63</nowiki>.</ref> | |||
* MDS bi-''TP53'' supersedes other genetically and morphologically defined MDS entities. By definition, in addition to the requirement for evidence of biallelic ''TP53'' inactivation, general criteria for diagnosis of MDS must be met and diagnostic criteria for acute myeloid leukemia must not be met. Acute erythroid leukemia, in which ''TP53'' mutations are common, must be specifically excluded by morphologic and/or immunophenotypic assessment.<ref name=":22" /> | |||
The <u>clinical features</u> of this disease are detailed below: | |||
* Signs and symptoms are typically nonspecific and related to cytopenias (unified thresholds for cytopenias in WHO5 diagnostic categories are detailed below, though these must be interpreted in the context of laboratory reference ranges, patient sex, and relevant comorbidities). ''TP53'' mutations show a strong association with thrombocytopenia in MDS.<ref name=":0" /><ref name=":1" /> | |||
*Anemia (hemoglobin < 130 g/L in males, < 120 g/L in females) | |||
**Pallor, fatigue | |||
*Neutropenia (absolute neutrophil count < 1.8x10<sup>9</sup>/L) | |||
**Infection | |||
*Thrombocytopenia (platelet count < 150x10<sup>9</sup>/L) | |||
**Bruising, petechiae, bleeding | |||
* MDS-bi''TP53'' is a high-risk disease, with increased risk of leukemic transformation and decreased overall survival; this elevated risk is independent of IPSS-R risk stratification and persists in the context of allogeneic hematopoietic stem cell transplantation. In the absence of comprehensive assessment for copy number losses or copy neutral LOH affecting the ''TP53'' locus, evidence suggests that the presence of a ''TP53'' mutation at high (>40%) VAF, particularly in the context of a complex karyotype, may be associated with a similarly poor prognosis to MDS-bi''TP53''.<ref name=":0" /><ref name=":2" /><ref>{{Cite journal|last=Sallman|first=D. A.|last2=Komrokji|first2=R.|last3=Vaupel|first3=C.|last4=Cluzeau|first4=T.|last5=Geyer|first5=S. M.|last6=McGraw|first6=K. L.|last7=Al Ali|first7=N. H.|last8=Lancet|first8=J.|last9=McGinniss|first9=M. J.|date=2016-03|title=Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/26514544|journal=Leukemia|volume=30|issue=3|pages=666–673|doi=10.1038/leu.2015.304|issn=1476-5551|pmc=7864381|pmid=26514544}}</ref><ref>{{Cite journal|last=Grob|first=Tim|last2=Al Hinai|first2=Adil S. A.|last3=Sanders|first3=Mathijs A.|last4=Kavelaars|first4=François G.|last5=Rijken|first5=Melissa|last6=Gradowska|first6=Patrycja L.|last7=Biemond|first7=Bart J.|last8=Breems|first8=Dimitri A.|last9=Maertens|first9=Johan|date=2022-04-14|title=Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/35108372|journal=Blood|volume=139|issue=15|pages=2347–2354|doi=10.1182/blood.2021014472|issn=1528-0020|pmid=35108372}}</ref> | |||
* Signs and symptoms - Pallor; Fatigue; Infection; Bruising; Bleeding; Petechiae | |||
* Laboratory findings - Anemia (hemoglobin < 130 g/L in males, < 120 g/L in females); Neutropenia (neutrophils < 1.8x10<sup>9</sup>/L); Thrombocytopenia (platelets < 150x10<sup>9</sup>/L); Circulating blasts (+/-); Elevated lactate dehydrogenase (+/-) | |||
The <u>sites of involvement</u> of this disease are detailed below: | |||
* Bone marrow and peripheral blood; rarely, extramedullary proliferations occur.<ref>{{Cite journal|last=Fan|first=N.|last2=Lavu|first2=S.|last3=Hanson|first3=C. A.|last4=Tefferi|first4=A.|date=2018-11-19|title=Extramedullary hematopoiesis in the absence of myeloproliferative neoplasm: Mayo Clinic case series of 309 patients|url=https://pubmed.ncbi.nlm.nih.gov/30455416|journal=Blood Cancer Journal|volume=8|issue=12|pages=119|doi=10.1038/s41408-018-0156-6|issn=2044-5385|pmc=6242913|pmid=30455416}}</ref> | |||
The <u>morphologic features</u> of this disease are detailed below: | |||
* Morphologic dysplasia is the hallmark of MDS, including MDS-bi''TP53''; by definition, at least one lineage. ''TP53'' mutations in MDS have been associated with particularly severe granulocytic dysplasia and with increased frequency of bone marrow blasts.<ref name=":0" /><ref name=":1" /><ref name=":4" /> ''TP53'' mutations are enriched in MDS associated with bone marrow fibrosis.<ref name=":5" /><ref name=":6" /> | |||
{| class="wikitable" | |||
!Hematopoietic lineage | |||
!Characteristic dysplastic features | |||
|- | |||
|'''Erythroid''' | |||
|Nuclear budding | |||
Internuclear bridging | |||
Multinuclearity | |||
Karyorrhexis | |||
Megaloblastosis | |||
Cytoplasmic vacuolation | |||
Ring sideroblasts | |||
Periodic acid Schiff positivity | |||
|- | |||
|'''Granulocytic''' | |||
|Nuclear hyposegmentation (Pelgeroid changes) | |||
Nuclear hypersegmentation | |||
Cytoplasmic hypogranularity | |||
Abnormally small cell size | |||
Auer rods | |||
Pseudo-Chédiak–Higashi granules | |||
|- | |||
|'''Megakaryocytic''' | |||
|Nuclear hypolobation | |||
Widely separated nuclear lobes | |||
Micromegakaryocytes | |||
|} | |||
The <u>immunophenotype</u> of this disease is detailed below: | |||
* Immunophenotyping by flow cytometry using assays designed to detect abnormal numbers, light scatter characteristics, and antigen expression patterns of hematopoietic cells can provide useful data supportive of a diagnosis of MDS (and aid in blast enumeration); however, these findings are not specific to MDS-bi''TP53'' and are not formalized in current diagnostic criteria.<ref name=":2" /><ref name=":7" /> | |||
* Immunohistochemical evaluation of TP53 protein expression in bone marrow specimens can be used to inform ''TP53'' mutation status. Several studies evaluating TP53 protein expression in bone marrow specimens have consistently demonstrated nuclear overexpression (thought to result from stabilization of TP53 resulting from dominant negative mutations), when present in an increased fraction of cells, to be associated with pathogenic ''TP53'' mutation and to be similarly predictive of poor outcomes.<ref name=":3" /><ref name=":8" /><ref name=":9" /><ref name=":10" /><ref name=":11" /> Complete absence of TP53 expression demonstrable by immunohistochemistry has similarly been associated with ''TP53'' mutation (typically frameshift, nonsense, and splice site, often with coexisting copy loss).<ref name=":3" /> <br /> | |||
==Links== | ==Links== | ||