HAEM5:Myelodysplastic neoplasm with biallelic TP53 inactivation: Difference between revisions

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MDS bi-''TP53'' is strongly associated with karyotype complexity, with a higher average number of cytogenetic abnormalities (rearrangements, copy gains, and copy losses) relative to MDS with unmutated ''TP53'' or with monoallelic mutation, with particular predilection for recurrent copy number losses.<ref name=":1" /><ref name=":0" /> Recurrent chromosomal gains, losses, and regions of LOH described which have been observed at higher frequency in MDS-bi''TP53'' include<ref name=":0" /><ref name=":2" /><ref name=":1" />:

* 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" />

* 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" />

* 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" />

* 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 < 1.8x10⁹/L); Thrombocytopenia (platelets < 150x10⁹/L); Circulating blasts (+/-); Elevated lactate dehydrogenase (+/-)

* 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>

* 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" />

* 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 />