Difference between revisions of "Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Unclassifiable"

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==Cancer Category/Type==
 
==Cancer Category/Type==
  
Put your text here
+
Myelodysplastic/Myeloproliferative Neoplasm (MDS/MPN)
  
 
==Cancer Sub-Classification / Subtype==
 
==Cancer Sub-Classification / Subtype==
  
Put your text here
+
Myelodysplastic / myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)
  
 
==Definition / Description of Disease==
 
==Definition / Description of Disease==
  
Put your text here
+
MDS/MPN-U are a heterogeneous group of myeloid neoplasms meeting the criteria for MDS/MPN at onset, without the defining features of one of the other categories of MDS/MPN (CMML, JMML, aCML or MDS/MPN-RS-T). <ref name=":0">Orazi A, et al., (2017). Myelodysplastic / myeloproliferative neoplasm, unclassifiable, 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, p95-96.</ref><ref name=":1">{{Cite journal|last=Ti|first=Mughal|last2=Nc|first2=Cross|last3=E|first3=Padron|last4=Rv|first4=Tiu|last5=M|first5=Savona|last6=L|first6=Malcovati|last7=R|first7=Tibes|last8=Rs|first8=Komrokji|last9=Jj|first9=Kiladjian|date=2015|title=An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/26341525/|language=en|doi=10.3324/haematol.2014.114660|pmc=PMC4800699|pmid=26341525}}</ref> This is the most poorly characterised of the MDS/MPN subgroups <ref name=":2">{{Cite journal|last=P|first=Bose|last2=A|first2=Nazha|last3=Rs|first3=Komrokji|last4=Kp|first4=Patel|last5=Sa|first5=Pierce|last6=N|first6=Al-Ali|last7=A|first7=Sochacki|last8=A|first8=Shaver|last9=W|first9=Ma|date=2018|title=Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable|url=https://pubmed.ncbi.nlm.nih.gov/30242087/|language=en|doi=10.1182/blood-2018-05-848473|pmc=PMC6236463|pmid=30242087}}</ref>.
 +
 
 +
*< 20% blasts in the peripheral blood and bone marrow
 +
*Clinical and morphological features of a category of MDS
 +
**'''excluding''' any case meeting the criteria for MDS with isolated del(5q)
 +
*Platelet count of ≥ 450 ×10/L with bone marrow megakaryocytic proliferation and/or a white bood cell count of ≥ 13 × 10<sup>9</sup>/L
 +
*Myelodysplastic / myeloproliferative features not explained by recent cytotoxic or growth factor therapy
 +
*Excludes cases with ''PDGFRA'', ''PDGFRB'' and ''FGFR1'' rearrangement and ''PCM1-JAK2'' <ref name=":0" />
 +
 
 +
Well-defined MPN which subsequently develop dysplastic features and progress to a more aggressive phase are excluded from this category.
 +
 
 +
When an underlying MPN has not been identified, the category of MDS/MPN-U is appropriate. <ref name=":0" />
 +
 
 +
Palomo ''et al.'' <ref name=":3">{{Cite journal|last=L|first=Palomo|last2=M|first2=Meggendorfer|last3=S|first3=Hutter|last4=S|first4=Twardziok|last5=V|first5=Adema|last6=I|first6=Fuhrmann|last7=F|first7=Fuster-Tormo|last8=B|first8=Xicoy|last9=L|first9=Zamora|date=2020|title=Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/32573691/|language=en|pmid=32573691}}</ref> defined further sub-categories of MDS/MPN-U based on the molecular signature. See [[Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Unclassifiable#Gene Mutations .28SNV.2FINDEL.29|Gene Mutations]] below.
  
 
==Synonyms / Terminology==
 
==Synonyms / Terminology==
  
Put your text here
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*Chronic myelodysplastic / myeloproliferative disease (no longer used)
 +
*Mixed myeloproliferative / myelodysplastic syndrome, unclassifiable
 +
*Overlap syndrome, unclassifiable <ref name=":0" /><ref name=":1" />
  
 
==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
  
Put your text here
+
*Less than 5% of myeloid malignancies<ref>{{Cite journal|last=L|first=Cannella|last2=M|first2=Breccia|last3=R|first3=Latagliata|last4=A|first4=Frustaci|last5=G|first5=Alimena|date=2008|title=Clinical and prognostic features of patients with myelodysplastic/myeloproliferative syndrome categorized as unclassified (MDS/MPD-U) by WHO classification|url=https://pubmed.ncbi.nlm.nih.gov/17709138/|language=en|pmid=17709138}}</ref>
 +
*Median age: reports vary from 70 <ref name=":1" /> to 75 <ref name=":2" />
 +
*Male:female ratio 2:1 <ref name=":1" /><ref name=":3" />
  
 
==Clinical Features==
 
==Clinical Features==
  
Put your text here
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*Overlap with [[Myelodysplastic Syndromes (MDS)|MDS]] and [[Myeloproliferative Neoplasms (MPN)|MPN]] <ref name=":0" />
 +
*Clinically the most heterogeneous of the MDS/MPN <ref name=":3" />
 +
*Does not have features that define it as belonging to any of the other categories of MDS/MPN <ref name=":0" /><ref name=":1" />
  
 
==Sites of Involvement==
 
==Sites of Involvement==
  
Put your text here
+
*Peripheral blood and bone marrow always involved
 +
*Extramedullary tissues may be involved <ref name=":0" />
  
 
==Morphologic Features==
 
==Morphologic Features==
  
Put your text here
+
Co-occurrence of myeloid lineages with (i) ineffective and/or dysplastic proliferation and (ii) effective proliferation with or without dysplasia
 +
 
 +
*Usually with anaemia, with or without macrocytosis
 +
*Thrombocytosis (platelets ≥ 450 x 10<sup>9</sup>/L) or leucocytosis (white blood cells ≥ 13 x 10<sup>9</sup>/L)
 +
*Dysgranulopoiesis in about 50% of cases
 +
*Giant or hypogranular platelets in some
 +
*Dysmegakaryopoiesis with megakaryocytes resembling those in MDS in >50% of cases, otherwise varying proportions of MDS-like and MPN-like megakaryocytes
 +
*No dysmegakaryopoiesis in <10% of cases
 +
*Blasts < 20% in bone marrow and peripheral blood
 +
*Proliferation in any or all of myeloid lineages in bone marrow biopsy
 +
*≥ 10% of at least one cell line <ref name=":0" />
 +
 
 +
MDS/MPN-U sub-categories described by Palomo ''et al.'' <ref name=":3" /> tend to have:
 +
 
 +
*CMML-like: higher monocyte count
 +
*aCML-like: higher white blood cell count
 +
*MDS/MPN-RS-T-like: higher ring sideroblast percentage
 +
*''TP53'': more anaemia and higher blast percentage
 +
*other: ''JAK2'' mutations correlated with thrombocytosis
  
 
==Immunophenotype==
 
==Immunophenotype==
  
Put your text here and/or fill in the table
+
May be similar to that of [[Myelodysplastic Syndromes (MDS)|MDS]] or [[Myeloproliferative Neoplasms (MPN)|MPN]] <ref name=":0" />
 
 
{| class="wikitable sortable"
 
|-
 
!Finding!!Marker
 
|-
 
|Positive (universal)||EXAMPLE CD1
 
|-
 
|Positive (subset)||EXAMPLE CD2
 
|-
 
|Negative (universal)||EXAMPLE CD3
 
|-
 
|Negative (subset)||EXAMPLE CD4
 
|}
 
  
 
==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
  
Put your text here and/or fill in the table
+
*None identified
 +
*''BCR-ABL1'' fusion should be excluded
 +
*Absence of ''PDGFRA'', ''PDGFRB'' and ''FGFR1'' rearrangements, absence of ''PCM1-JAK2'' fusion <ref name=":0" />
  
{| 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==
  
Put your text here
+
*None specific to MDS/MPN-U
 +
*Abnormal karyotype 43% across four studies (11/38 <ref>{{Cite journal|last=M|first=Meggendorfer|last2=S|first2=Jeromin|last3=C|first3=Haferlach|last4=W|first4=Kern|last5=T|first5=Haferlach|date=2018|title=The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/29700173/|language=en|doi=10.3324/haematol.2017.183160|pmc=PMC5927999|pmid=29700173}}</ref>; 48/102 <ref name=":3" />; 23/65 <ref name=":4">{{Cite journal|last=Sa|first=Wang|last2=Rp|first2=Hasserjian|last3=Ps|first3=Fox|last4=Hj|first4=Rogers|last5=Jt|first5=Geyer|last6=D|first6=Chabot-Richards|last7=E|first7=Weinzierl|last8=J|first8=Hatem|last9=J|first9=Jaso|date=2014|title=Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/24627528/|language=en|doi=10.1182/blood-2014-02-553800|pmc=PMC4067498|pmid=24627528}}</ref>; 43/85 <ref name=":5">{{Cite journal|last=Cd|first=DiNardo|last2=N|first2=Daver|last3=N|first3=Jain|last4=N|first4=Pemmaraju|last5=C|first5=Bueso-Ramos|last6=Cc|first6=Yin|last7=S|first7=Pierce|last8=E|first8=Jabbour|last9=Je|first9=Cortes|date=2014|title=Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy|url=https://pubmed.ncbi.nlm.nih.gov/24492324/|language=en|doi=10.1038/leu.2014.8|pmc=PMC3981947|pmid=24492324}}</ref>)
 +
*Complex karyotype 10% across three studies (12/102 <ref name=":3" />; 2/65 <ref name=":4" />; 10/85 <ref name=":5" />)
  
 
==Genomic Gain/Loss/LOH==
 
==Genomic Gain/Loss/LOH==
  
Put your text here and/or fill in the table
+
*isochromosome of 17q <ref>{{Cite journal|last=Barbouti|first=Aikaterini|last2=Stankiewicz|first2=Pawel|last3=Nusbaum|first3=Chad|last4=Cuomo|first4=Christina|last5=Cook|first5=April|last6=Höglund|first6=Mattias|last7=Johansson|first7=Bertil|last8=Hagemeijer|first8=Anne|last9=Park|first9=Sung-Sup|date=2004|title=The Breakpoint Region of the Most Common Isochromosome, i(17q), in Human Neoplasia Is Characterized by a Complex Genomic Architecture with Large, Palindromic, Low-Copy Repeats|url=https://linkinghub.elsevier.com/retrieve/pii/S0002929707619399|journal=The American Journal of Human Genetics|language=en|volume=74|issue=1|pages=1–10|doi=10.1086/380648|pmc=PMC1181896|pmid=14666446}}</ref> <ref name=":0" /> <ref>{{Cite journal|last=R|first=Kanagal-Shamanna|last2=Ce|first2=Bueso-Ramos|last3=B|first3=Barkoh|last4=G|first4=Lu|last5=S|first5=Wang|last6=G|first6=Garcia-Manero|last7=S|first7=Vadhan-Raj|last8=D|first8=Hoehn|last9=Lj|first9=Medeiros|date=2012|title=Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53|url=https://pubmed.ncbi.nlm.nih.gov/22038701/|language=en|pmid=22038701}}</ref> <ref name=":6">{{Cite journal|last=A|first=Orazi|last2=U|first2=Germing|date=2008|title=The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features|url=https://pubmed.ncbi.nlm.nih.gov/18480833/|language=en|pmid=18480833}}</ref>; incidence in one study 1/65 cases <ref name=":4" />
 +
*+ 8
 +
**23% across two studies (26/102 <ref name=":3" />; 12/65 <ref name=":4" />)
 +
**isolated +8, 16% across two studies (17/102 <ref name=":3" />; 13/85 <ref name=":5" />)
 +
*-7/del(7q)
 +
**10% across two studies (12/102 <ref name=":3" />; 4/65 <ref name=":4" />)
 +
**isolated -7/del(7q), 5% (5/102 <ref name=":3" />)
 +
 
 +
*Excludes any case with isolated del(5q) (even if ''JAK2'' mutated) <ref name=":0" /> - these should be classified as MDS with isolated del(5q)
 +
 
 +
Very few recurrent gains and losses were identified below the level of cytogenetic detection in one study <ref name=":3" />.
  
{| 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)==
  
Put your text here and/or fill in the tables
+
Amongst the MDS/MPN subtypes, MDS/MPN-U has the most heterogeneous mutation profile. In one study it was most strongly correlated with ''U2AF1'' and ''TP53'' mutations <ref name=":3" />.
 +
 
 +
No mutations are specific for any MDS/MPN, including MDS/MPN-U <ref name=":3" />.
 +
 
 +
The most common or significant mutations in MDS/MPN-U are listed below with the frequencies and some mutation detail as reported in different publications:
 +
 
 +
*''ASXL1:'' 21% <ref name=":2" />; 53% <ref name=":3" />
 +
*''TET2:'' 21% <ref name=":2" />; 37% <ref name=":3" />
 +
*''JAK2:'' 19% <ref name=":2" />; 25% <ref name=":3" />; 18% <ref name=":4" />
 +
**V617F <ref name=":2" />
 +
*''SRSF2:'' 15% <ref name=":2" />; 23% <ref name=":3" />
 +
**P95 residue <ref name=":2" />
 +
*''EZH2:'' 14% <ref name=":2" />; 25% <ref name=":3" />
 +
*''STAG2:'' 16% <ref name=":3" />
 +
*''U2AF1:'' 11% <ref name=":2" /> 19% <ref name=":3" />
 +
**most mutatons in Q157 <ref name=":2" />
 +
*''RUNX1:'' 11% <ref name=":2" />; 17% <ref name=":3" />
 +
*''TP53:'' 8% <ref name=":2" />; 12% <ref name=":3" />
 +
*''ZBTB33:'' 5% <ref name=":3" />
 +
**novel to MDS/MPN-U in a study of 367 MDS/MPN <ref name=":3" />
 +
 
 +
Palomo ''et al'' identified specific mutation combinations that mimicked the other MDS/MPN subtypes and allowed MDS/MPN-U to be assigned to one of five MDS/MPN-U sub-categories <ref name=":3" />: 
 +
 
 +
(The first three are most similar to one of the three other adult subgroups of MDS/MPN)
 +
 
 +
1. CMML-like (''TET2/SRSF2'')
 +
 
 +
2. aCML-like (''ASXL1/EZH2'')
 +
 
 +
3. MDS/MPN-RS-T-like (''SF3B1'' or ''DNMT3A/SF3B1'')
 +
 
 +
4. TP53 sub-category (mono- or bi-allelic ''TP53'' mutation; more anaemia and higher blast count)
 +
 
 +
5. other (no distinctive signature but enriched for ''U2AF1, JAK2, ASXL1'' mutations; ''JAK2'' mutations correlated with thrombocytosis)
  
{| class="wikitable sortable"
 
|-
 
!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===
 
===Other Mutations===
{| class="wikitable sortable"
+
The presence of ''TET2'', ''NRAS'', ''RUNX1'', ''CBL'', ''SETBP1'' or ''ASXL1'' mutation may help confirm a suspected diagnosis <ref name=":0" />.
|-
+
 
!Type!!Gene/Region/Other
+
If a ''SF3B1'' mutation is present, consider whether it is MDS/MPN-RS-T or progression from MDS with ring sideroblasts <ref name=":0" />.
|-
+
 
|Concomitant Mutations||EXAMPLE IDH1 R123H
+
MPN driver mutations (e.g. ''JAK2'', ''MPL'' or ''CALR'' mutation'')'' may be present, but if pre-existing MPN is not documented, an MDS/MPN-U designation is justified <ref name=":0" />.
|-
+
 
|Secondary Mutations||EXAMPLE Trisomy 7
+
There is a significant likelihood of AML developing if there is ''ASXL1'' and ''SRSF2'' co-mutation <ref name=":2" />.
|-
 
|Mutually Exclusive||EXAMPLE EGFR Amplification
 
|}
 
  
 
==Epigenomics (Methylation)==
 
==Epigenomics (Methylation)==
  
Put your text here
+
Not known
  
 
==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
  
Put your text here
+
*Major drivers / early mutations in epigenetic regulators (''ASXL1, TET2)'' and splicing factors (''SRSF2'') <ref name=":2" /> <ref name=":3" />
 +
*Secondary mutations in signaling pathway genes (''JAK2'') <ref name=":3" />
  
 
==Diagnostic Testing Methods==
 
==Diagnostic Testing Methods==
  
Put your text here
+
*Conventional chromosome analysis
 +
*Palomo ''et al'' recommend targeted sequencing of MDS/MPN-U <ref name=":3" />
  
 
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
 
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
  
Put your text here
+
*Prognosis is variable and not well documented <ref name=":0" />
 +
*There are few data regarding an appropriate prognostic scoring system <ref name=":0" />, but IPSS-R <ref name=":2" />or IPSS <ref name=":5" /> have been prognostically useful
 +
*Median overall survival (OS) from various reports: 80 months <ref name=":3" />; 21.8 months <ref name=":4" />; 12 months <ref name=":2" />
 +
*Leukaemia-free survival: 18.9 months <ref name=":4" />; 10.8 months <ref name=":2" />
 +
*Leukaemic transformation: 10% <ref name=":3" />; 16% after a median of 10.8 months <ref name=":2" />; 
 +
**ASXL1/SRSF2 co-mutation is a significant risk factor <ref name=":2" />
 +
*Abnormal karyotype associated with inferior OS <ref name=":3" />
 +
*''ASXL1, EZH2, STAG2'' mutations associated with shorter OS <ref name=":2" /><ref name=":3" />
 +
*Targeted sequencing may be useful for assessing prognostic impact and making clinical decisions <ref name=":3" />.
 +
**Molecular classification into sub-categories had the strongest prognostic impact in a study by Palomo ''et al.'' <ref name=":3" />:
 +
***MDS/MPN-RS-T-like: most favourable prognosis
 +
***aCML-like: high risk
 +
***"TP53": least favourable prognosis
 +
*“Treatment is based on therapies used for MDS or MPN and is guided by symptoms and/or cytopenias” and can include growth factors for leukocytosis or cytoreductive therapies for cytopenias <ref name=":0" />.
  
 
==Familial Forms==
 
==Familial Forms==
  
Put your text here
+
Not known
  
 
==Other Information==
 
==Other Information==
  
Put your text here
+
Refractory anemia with ring sideroblasts and thrombosis (RARS-T) fell within this category prior to the 2016 WHO edition <ref name=":0" /><ref name=":6" /> but now forms a distinct category, MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).
  
 
==Links==
 
==Links==

Revision as of 13:16, 28 July 2020

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Primary Author(s)*

Ruth MacKinnon PhD

Victorian Cancer Cytogenetics Service

Melbourne, Australia

Cancer Category/Type

Myelodysplastic/Myeloproliferative Neoplasm (MDS/MPN)

Cancer Sub-Classification / Subtype

Myelodysplastic / myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)

Definition / Description of Disease

MDS/MPN-U are a heterogeneous group of myeloid neoplasms meeting the criteria for MDS/MPN at onset, without the defining features of one of the other categories of MDS/MPN (CMML, JMML, aCML or MDS/MPN-RS-T). [1][2] This is the most poorly characterised of the MDS/MPN subgroups [3].

  • < 20% blasts in the peripheral blood and bone marrow
  • Clinical and morphological features of a category of MDS
    • excluding any case meeting the criteria for MDS with isolated del(5q)
  • Platelet count of ≥ 450 ×10/L with bone marrow megakaryocytic proliferation and/or a white bood cell count of ≥ 13 × 109/L
  • Myelodysplastic / myeloproliferative features not explained by recent cytotoxic or growth factor therapy
  • Excludes cases with PDGFRA, PDGFRB and FGFR1 rearrangement and PCM1-JAK2 [1]

Well-defined MPN which subsequently develop dysplastic features and progress to a more aggressive phase are excluded from this category.

When an underlying MPN has not been identified, the category of MDS/MPN-U is appropriate. [1]

Palomo et al. [4] defined further sub-categories of MDS/MPN-U based on the molecular signature. See Gene Mutations below.

Synonyms / Terminology

  • Chronic myelodysplastic / myeloproliferative disease (no longer used)
  • Mixed myeloproliferative / myelodysplastic syndrome, unclassifiable
  • Overlap syndrome, unclassifiable [1][2]

Epidemiology / Prevalence

  • Less than 5% of myeloid malignancies[5]
  • Median age: reports vary from 70 [2] to 75 [3]
  • Male:female ratio 2:1 [2][4]

Clinical Features

  • Overlap with MDS and MPN [1]
  • Clinically the most heterogeneous of the MDS/MPN [4]
  • Does not have features that define it as belonging to any of the other categories of MDS/MPN [1][2]

Sites of Involvement

  • Peripheral blood and bone marrow always involved
  • Extramedullary tissues may be involved [1]

Morphologic Features

Co-occurrence of myeloid lineages with (i) ineffective and/or dysplastic proliferation and (ii) effective proliferation with or without dysplasia

  • Usually with anaemia, with or without macrocytosis
  • Thrombocytosis (platelets ≥ 450 x 109/L) or leucocytosis (white blood cells ≥ 13 x 109/L)
  • Dysgranulopoiesis in about 50% of cases
  • Giant or hypogranular platelets in some
  • Dysmegakaryopoiesis with megakaryocytes resembling those in MDS in >50% of cases, otherwise varying proportions of MDS-like and MPN-like megakaryocytes
  • No dysmegakaryopoiesis in <10% of cases
  • Blasts < 20% in bone marrow and peripheral blood
  • Proliferation in any or all of myeloid lineages in bone marrow biopsy
  • ≥ 10% of at least one cell line [1]

MDS/MPN-U sub-categories described by Palomo et al. [4] tend to have:

  • CMML-like: higher monocyte count
  • aCML-like: higher white blood cell count
  • MDS/MPN-RS-T-like: higher ring sideroblast percentage
  • TP53: more anaemia and higher blast percentage
  • other: JAK2 mutations correlated with thrombocytosis

Immunophenotype

May be similar to that of MDS or MPN [1]

Chromosomal Rearrangements (Gene Fusions)

  • None identified
  • BCR-ABL1 fusion should be excluded
  • Absence of PDGFRA, PDGFRB and FGFR1 rearrangements, absence of PCM1-JAK2 fusion [1]

Characteristic Chromosomal Aberrations / Patterns

  • None specific to MDS/MPN-U
  • Abnormal karyotype 43% across four studies (11/38 [6]; 48/102 [4]; 23/65 [7]; 43/85 [8])
  • Complex karyotype 10% across three studies (12/102 [4]; 2/65 [7]; 10/85 [8])

Genomic Gain/Loss/LOH

  • isochromosome of 17q [9] [1] [10] [11]; incidence in one study 1/65 cases [7]
  • + 8
    • 23% across two studies (26/102 [4]; 12/65 [7])
    • isolated +8, 16% across two studies (17/102 [4]; 13/85 [8])
  • -7/del(7q)
    • 10% across two studies (12/102 [4]; 4/65 [7])
    • isolated -7/del(7q), 5% (5/102 [4])
  • Excludes any case with isolated del(5q) (even if JAK2 mutated) [1] - these should be classified as MDS with isolated del(5q)

Very few recurrent gains and losses were identified below the level of cytogenetic detection in one study [4].

Gene Mutations (SNV/INDEL)

Amongst the MDS/MPN subtypes, MDS/MPN-U has the most heterogeneous mutation profile. In one study it was most strongly correlated with U2AF1 and TP53 mutations [4].

No mutations are specific for any MDS/MPN, including MDS/MPN-U [4].

The most common or significant mutations in MDS/MPN-U are listed below with the frequencies and some mutation detail as reported in different publications:

Palomo et al identified specific mutation combinations that mimicked the other MDS/MPN subtypes and allowed MDS/MPN-U to be assigned to one of five MDS/MPN-U sub-categories [4]:

(The first three are most similar to one of the three other adult subgroups of MDS/MPN)

1. CMML-like (TET2/SRSF2)

2. aCML-like (ASXL1/EZH2)

3. MDS/MPN-RS-T-like (SF3B1 or DNMT3A/SF3B1)

4. TP53 sub-category (mono- or bi-allelic TP53 mutation; more anaemia and higher blast count)

5. other (no distinctive signature but enriched for U2AF1, JAK2, ASXL1 mutations; JAK2 mutations correlated with thrombocytosis)

Other Mutations

The presence of TET2, NRAS, RUNX1, CBL, SETBP1 or ASXL1 mutation may help confirm a suspected diagnosis [1].

If a SF3B1 mutation is present, consider whether it is MDS/MPN-RS-T or progression from MDS with ring sideroblasts [1].

MPN driver mutations (e.g. JAK2, MPL or CALR mutation) may be present, but if pre-existing MPN is not documented, an MDS/MPN-U designation is justified [1].

There is a significant likelihood of AML developing if there is ASXL1 and SRSF2 co-mutation [3].

Epigenomics (Methylation)

Not known

Genes and Main Pathways Involved

  • Major drivers / early mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SRSF2) [3] [4]
  • Secondary mutations in signaling pathway genes (JAK2) [4]

Diagnostic Testing Methods

  • Conventional chromosome analysis
  • Palomo et al recommend targeted sequencing of MDS/MPN-U [4]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Prognosis is variable and not well documented [1]
  • There are few data regarding an appropriate prognostic scoring system [1], but IPSS-R [3]or IPSS [8] have been prognostically useful
  • Median overall survival (OS) from various reports: 80 months [4]; 21.8 months [7]; 12 months [3]
  • Leukaemia-free survival: 18.9 months [7]; 10.8 months [3]
  • Leukaemic transformation: 10% [4]; 16% after a median of 10.8 months [3]
    • ASXL1/SRSF2 co-mutation is a significant risk factor [3]
  • Abnormal karyotype associated with inferior OS [4]
  • ASXL1, EZH2, STAG2 mutations associated with shorter OS [3][4]
  • Targeted sequencing may be useful for assessing prognostic impact and making clinical decisions [4].
    • Molecular classification into sub-categories had the strongest prognostic impact in a study by Palomo et al. [4]:
      • MDS/MPN-RS-T-like: most favourable prognosis
      • aCML-like: high risk
      • "TP53": least favourable prognosis
  • “Treatment is based on therapies used for MDS or MPN and is guided by symptoms and/or cytopenias” and can include growth factors for leukocytosis or cytoreductive therapies for cytopenias [1].

Familial Forms

Not known

Other Information

Refractory anemia with ring sideroblasts and thrombosis (RARS-T) fell within this category prior to the 2016 WHO edition [1][11] but now forms a distinct category, MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

Links

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References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 Orazi A, et al., (2017). Myelodysplastic / myeloproliferative neoplasm, unclassifiable, 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, p95-96.
  2. 2.0 2.1 2.2 2.3 2.4 Ti, Mughal; et al. (2015). "An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms". doi:10.3324/haematol.2014.114660. PMC 4800699. PMID 26341525.CS1 maint: PMC format (link)
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 P, Bose; et al. (2018). "Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable". doi:10.1182/blood-2018-05-848473. PMC 6236463. PMID 30242087.CS1 maint: PMC format (link)
  4. 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 4.25 4.26 4.27 4.28 4.29 4.30 4.31 4.32 4.33 L, Palomo; et al. (2020). "Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms". PMID 32573691 Check |pmid= value (help).
  5. L, Cannella; et al. (2008). "Clinical and prognostic features of patients with myelodysplastic/myeloproliferative syndrome categorized as unclassified (MDS/MPD-U) by WHO classification". PMID 17709138.
  6. M, Meggendorfer; et al. (2018). "The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms". doi:10.3324/haematol.2017.183160. PMC 5927999. PMID 29700173.CS1 maint: PMC format (link)
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Sa, Wang; et al. (2014). "Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms". doi:10.1182/blood-2014-02-553800. PMC 4067498. PMID 24627528.CS1 maint: PMC format (link)
  8. 8.0 8.1 8.2 8.3 Cd, DiNardo; et al. (2014). "Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy". doi:10.1038/leu.2014.8. PMC 3981947. PMID 24492324.CS1 maint: PMC format (link)
  9. Barbouti, Aikaterini; et al. (2004). "The Breakpoint Region of the Most Common Isochromosome, i(17q), in Human Neoplasia Is Characterized by a Complex Genomic Architecture with Large, Palindromic, Low-Copy Repeats". The American Journal of Human Genetics. 74 (1): 1–10. doi:10.1086/380648. PMC 1181896. PMID 14666446.CS1 maint: PMC format (link)
  10. R, Kanagal-Shamanna; et al. (2012). "Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53". PMID 22038701.
  11. 11.0 11.1 A, Orazi; et al. (2008). "The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features". PMID 18480833.

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EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, 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, p129-171.

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