View source for HAEM4Backup:Myeloproliferative Neoplasm (MPN), Unclassifiable

==Primary Author(s)==
Thomas Lee, MD, PhD, University of California, Los Angeles

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==Cancer Category/Type==

Myeloproliferative neoplasm

==Cancer Sub-Classification / Subtype==

Myeloproliferative neoplasm, unclassifiable

==Definition / Description of Disease==

The myeloproliferative neoplasm, unclassifiable (MPN, U) designation is used for cases with definite features of a myeloproliferative neoplasm (MPN) that fail to meet the specific criteria needed for diagnosis or features of more than one myeloproliferative neoplasm, and has three main uses<ref name=":0">Kvasnicka HM, et al., (2017). 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, p129-171.</ref>. The first occurs in the early disease stage where the features needed to distinguish polycythemia vera, prefibrotic/early stage primary myelofibrosis, and essential thrombocythemia have not yet sufficiently developed. The second arises in the advanced stage where late stage features including severe myelofibrosis, osteosclerosis, dysplasia, and increased blasts mask the underlying diagnosis. Similarly, the underlying diagnosis cannot be determined due to a concurrent neoplasm or inflammatory condition in the third main use.

==Synonyms / Terminology==

Myeloproliferative disease, NOS; Chronic myeloproliferative disease, unclassifiable.

==Epidemiology / Prevalence==

While some reports have indicated that MPN, U accounts for 10-15% of MPNs<ref name=":0" /> with past controversy about the reproducibility of the WHO classification<ref>{{Cite journal|last=Barbui|first=T.|last2=Thiele|first2=J.|last3=Vannucchi|first3=A. M.|last4=Tefferi|first4=A.|date=2013-10|title=Problems and pitfalls regarding WHO-defined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia|url=https://pubmed.ncbi.nlm.nih.gov/23467025|journal=Leukemia|volume=27|issue=10|pages=1953–1958|doi=10.1038/leu.2013.74|issn=1476-5551|pmid=23467025}}</ref>, the revised 2016 WHO diagnostic criteria based on clinical, morphologic, and molecular features may potentially reduce the frequency to <5%<ref name=":0" />. Two studies have shown that 19 (27%) of 71 and 5 (45%) of 11 MPN, U cases classified according to 2008 WHO diagnostic criteria remained classified as MPN, U following 2016 WHO diagnostic criteria<ref name=":2">{{Cite journal|last=Iurlo|first=Alessandra|last2=Gianelli|first2=Umberto|last3=Cattaneo|first3=Daniele|last4=Thiele|first4=Juergen|last5=Orazi|first5=Attilio|date=2017-04|title=Impact of the 2016 revised WHO criteria for myeloproliferative neoplasms, unclassifiable: Comparison with the 2008 version|url=https://pubmed.ncbi.nlm.nih.gov/28109016|journal=American Journal of Hematology|volume=92|issue=4|pages=E48–E51|doi=10.1002/ajh.24657|issn=1096-8652|pmid=28109016}}</ref><ref name=":3">{{Cite journal|last=Yun|first=Jiwon|last2=Kim|first2=Jung-Ah|last3=Park|first3=Junseo|last4=Im|first4=Kyongok|last5=Lee|first5=Young Eun|last6=Jeong|first6=Dajeong|last7=Ryu|first7=Sohee|last8=Lim|first8=Kyu Min|last9=Kim|first9=Sung-Min|date=2020-09-02|title=Reclassification of subtypes in Philadelphia chromosome-negative myeloproliferative neoplasm by 2016 WHO diagnostic criteria: focus on the cases classified as myeloproliferative neoplasm, unclassifiable by the 2008 version|url=https://pubmed.ncbi.nlm.nih.gov/32876501|journal=Leukemia & Lymphoma|pages=1–5|doi=10.1080/10428194.2020.1808212|issn=1029-2403|pmid=32876501}}</ref>. 

In the United States from 2001-2012, the age-adjusted incidence rate was 4.8 per one million person-years (PY) with a median age of 73 years and a male-to-female incidence rate ratio of 1.42<ref>Srour SA, Devesa SS, Morton LM, Check DP, Curtis RE, Linet MS, Dores GM. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12. Br J Haematol. 2016 Aug;174(3):382-96. doi: 10.1111/bjh.14061. Epub 2016 Apr 7. Erratum in: Br J Haematol. 2017 Apr;177(2):331. PMID: 27061824; PMCID: PMC4961550.</ref>. A study of 71 2008 WHO diagnosed MPN,U cases indicated a median age of 61 years (range: 14 - 91 years) with males representing 43.7% of cases<ref name=":1">Gianelli U, Cattaneo D, Bossi A, Cortinovis I, Boiocchi L, Liu YC, Augello C, Bonometti A, Fiori S, Orofino N, Guidotti F, Orazi A, Iurlo A. The myeloproliferative neoplasms, unclassifiable: clinical and pathological considerations. Mod Pathol. 2017 Feb;30(2):169-179. doi: 10.1038/modpathol.2016.182. Epub 2016 Oct 14. Erratum in: Mod Pathol. 2017 Jul;30(7):1043. PMID: 27739437.</ref>. A study of 26 2016 WHO diagnosed MPN,U cases showed a median age of 44.3 years (range: 18.2 - 79.4 years) with males representing 27% of cases<ref name=":4">{{Cite journal|last=Rumi|first=Elisa|last2=Boveri|first2=Emanuela|last3=Bellini|first3=Marta|last4=Pietra|first4=Daniela|last5=Ferretti|first5=Virginia V.|last6=Sant'Antonio|first6=Emanuela|last7=Cavalloni|first7=Chiara|last8=Casetti|first8=Ilaria C.|last9=Roncoroni|first9=Elisa|date=2017-11-24|title=Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria|url=https://pubmed.ncbi.nlm.nih.gov/29254200|journal=Oncotarget|volume=8|issue=60|pages=101735–101744|doi=10.18632/oncotarget.21594|issn=1949-2553|pmc=5731910|pmid=29254200}}</ref>.

==Clinical Features==

The clinical features are similar to other MPNs and reflect the stage of disease<ref name=":0" />. The early stage can variably show thrombocytosis and leukocytosis with or without anemia and minimal to absent organomegaly. Splanchnic vein thrombosis may be present<ref>{{Cite journal|last=Gianelli|first=Umberto|last2=Iurlo|first2=Alessandra|last3=Cattaneo|first3=Daniele|last4=Bossi|first4=Anna|last5=Cortinovis|first5=Ivan|last6=Augello|first6=Claudia|last7=Moro|first7=Alessia|last8=Savi|first8=Federica|last9=Castelli|first9=Roberto|date=2015-05|title=Discrepancies between bone marrow histopathology and clinical phenotype in BCR-ABL1-negative myeloproliferative neoplasms associated with splanchnic vein thrombosis|url=https://pubmed.ncbi.nlm.nih.gov/25840747|journal=Leukemia Research|volume=39|issue=5|pages=525–529|doi=10.1016/j.leukres.2015.03.009|issn=1873-5835|pmid=25840747}}</ref>. Marked splenomegaly and/or hepatomegaly with cytopenias can be present with advanced disease.

==Sites of Involvement==

Blood and bone marrow are sites of involvement similar to other MPNs<ref name=":0" />. Extramedullary hematopoiesis involving the spleen and/or liver may be present in advanced cases.

==Morphologic Features==

The morphologic features are similar to other MPNs and reflect the stage of disease<ref name=":0" />. In the early stage, the peripheral blood may show thrombocytosis and variable neutrophilia. The bone marrow is most often hypercellular with increased megakaryopoiesis showing abnormal forms with clustering and variably increased granulopoiesis and erythropoiesis. Severe myelofibrosis, osteosclerosis, and myelodysplasia can be seen with advanced disease. The presence of ≥ 10% blasts in the peripheral blood or bone marrow and/or significant myelodysplasia indicates a transition to a more aggressive phase and cases initially diagnosed with 10-19% blasts are considered to be in accelerated phase<ref name=":0" />.

==Immunophenotype==

There is no defining immunophenotype.

==Chromosomal Rearrangements (Gene Fusions)==

There are no associated chromosomal rearrangements. There should be no ''BCR''-''ABL1'' or ''PCM1-JAK2'' fusion and no ''PDGFRA'', ''PDGFRB'', or ''FGFR1'' rearrangement. Rearrangements that have been reported include t(4;12)(q12;p13)<ref name=":5">{{Cite journal|last=Zhang|first=Ling|last2=Wang|first2=Man|last3=Wang|first3=Zheng|last4=Zeng|first4=Zhao|last5=Wen|first5=Lijun|last6=Xu|first6=Yi|last7=Yao|first7=Li|last8=Cen|first8=Jiannong|last9=Li|first9=Hongzhi|date=2020-10|title=Identification of a novel ETV6 truncated fusion gene in myeloproliferative neoplasm, unclassifiable with t(4;12)(q12;p13)|url=https://pubmed.ncbi.nlm.nih.gov/32734549|journal=Annals of Hematology|volume=99|issue=10|pages=2445–2447|doi=10.1007/s00277-020-04207-y|issn=1432-0584|pmid=32734549}}</ref>.
==Characteristic Chromosomal Aberrations / Patterns==

There are no characteristic chromosomal aberrations/patterns. Cytogenetic abnormalities have been described in four (5.6%) of 71 2008 WHO diagnosed cases<ref name=":1" /> and one (20%) of five 2016 WHO diagnosed cases<ref name=":3" />. Chromosomal aberrations that have been reported include trisomy 8<ref name=":1" /> and 46,XY,inv(12)(q15q24.1)<ref name=":3" />.

==Genomic Gain/Loss/LOH==

There are no characteristic genomic gain/loss/LOH.
==Gene Mutations (SNV/INDEL)==

Mutations in ''JAK2'', ''MPL'', and ''CALR'' are recurrent. A subset of cases have been reported to be negative for mutations in these three genes (i.e. triple negative). Limited studies have reported mutations in other genes including ''ASXL1''<ref name=":3" /> and ''ZRSR2''<ref name=":3" /><ref name=":5" />.

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|''JAK2''||V617F||Oncogene||GOF||72%<ref name=":1" />, 65%<ref name=":4" />
|-
|''MPL''
|W515L, Exon 10
|Oncogene
|GOF
|3%<ref name=":1" />, 4%<ref name=":4" />
|-
|''CALR''
|Type 1/Type 2/Other
|Oncogene
|GOF
|11%<ref name=":1" />, 60%<ref name=":3" />, 27%<ref name=":4" />
|-
|Triple Negative
|N/A
|N/A
|N/A
|3%<ref name=":1" />, 4%<ref name=":4" />
|}	
		
===Other Mutations===
{| class="wikitable sortable"
|-
!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==

Mutations in ''JAK2'', ''CALR'', and ''MPL'' lead to constitutive activation of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. ''JAK2'' V617F mutations affect signalling through the EPOR, MPL, and G-CSFR homodimeric receptors while ''CALR'' and ''MPL'' mutations affect signalling through MPL only<ref>{{Cite journal|last=Vainchenker|first=William|last2=Kralovics|first2=Robert|date=02 09, 2017|title=Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/28028029|journal=Blood|volume=129|issue=6|pages=667–679|doi=10.1182/blood-2016-10-695940|issn=1528-0020|pmid=28028029}}</ref>.

==Diagnostic Testing Methods==

Mutations in ''JAK2'' V617F, ''CALR'', and ''MPL'' can be detected through various molecular testing methodologies including allele specific PCR based methods, capillary electrophoresis fragment analysis, and/or next generation sequencing.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

Follow-up studies on a 6 - 12 month interval can provide additional information for classification<ref name=":0" />.

==Familial Forms==

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==Other Information==

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==Links==

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==References==
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<references />
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==Notes==
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