Myeloproliferative Neoplasm (MPN), Unclassifiable

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Primary Author(s)

Thomas Lee, MD, PhD, University of California, Los Angeles

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[1]. 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[1] with past controversy about the reproducibility of the WHO classification[2], the revised 2016 WHO diagnostic criteria based on clinical, morphologic, and molecular features may potentially reduce the frequency to <5%[1]. 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[3][4].

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[5]. 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[6]. 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[7].

Clinical Features

The clinical features are similar to other MPNs and reflect the stage of disease[1]. The early stage can variably show thrombocytosis and leukocytosis with or without anemia and minimal to absent organomegaly. Splanchnic vein thrombosis may be present[8]. 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[1]. 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[1]. 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[1].

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)[9].

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[6] and one (20%) of five 2016 WHO diagnosed cases[4]. Chromosomal aberrations that have been reported include trisomy 8[6] and 46,XY,inv(12)(q15q24.1)[4].

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[4] and ZRSR2[4][9].

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
JAK2 V617F Oncogene GOF 72%[6], 65%[7]
MPL W515L, Exon 10 Oncogene GOF 3%[6], 4%[7]
CALR Type 1/Type 2/Other Oncogene GOF 11%[6], 60%[4], 27%[7]
Triple Negative N/A N/A N/A 3%[6], 4%[7]

Other Mutations

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

Epigenomics (Methylation)

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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[10].

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[1].

Familial Forms

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Other Information

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Links

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References

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  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 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.
  2. Barbui, T.; et al. (2013-10). "Problems and pitfalls regarding WHO-defined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia". Leukemia. 27 (10): 1953–1958. doi:10.1038/leu.2013.74. ISSN 1476-5551. PMID 23467025. Check date values in: |date= (help)
  3. Iurlo, Alessandra; et al. (2017-04). "Impact of the 2016 revised WHO criteria for myeloproliferative neoplasms, unclassifiable: Comparison with the 2008 version". American Journal of Hematology. 92 (4): E48–E51. doi:10.1002/ajh.24657. ISSN 1096-8652. PMID 28109016. Check date values in: |date= (help)
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Yun, Jiwon; et al. (2020-09-02). "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". Leukemia & Lymphoma: 1–5. doi:10.1080/10428194.2020.1808212. ISSN 1029-2403. PMID 32876501 Check |pmid= value (help).
  5. 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.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 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.
  7. 7.0 7.1 7.2 7.3 7.4 Rumi, Elisa; et al. (2017-11-24). "Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria". Oncotarget. 8 (60): 101735–101744. doi:10.18632/oncotarget.21594. ISSN 1949-2553. PMC 5731910. PMID 29254200.
  8. Gianelli, Umberto; et al. (2015-05). "Discrepancies between bone marrow histopathology and clinical phenotype in BCR-ABL1-negative myeloproliferative neoplasms associated with splanchnic vein thrombosis". Leukemia Research. 39 (5): 525–529. doi:10.1016/j.leukres.2015.03.009. ISSN 1873-5835. PMID 25840747. Check date values in: |date= (help)
  9. 9.0 9.1 Zhang, Ling; et al. (2020-10). "Identification of a novel ETV6 truncated fusion gene in myeloproliferative neoplasm, unclassifiable with t(4;12)(q12;p13)". Annals of Hematology. 99 (10): 2445–2447. doi:10.1007/s00277-020-04207-y. ISSN 1432-0584. PMID 32734549 Check |pmid= value (help). Check date values in: |date= (help)
  10. Vainchenker, William; et al. (02 09, 2017). "Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms". Blood. 129 (6): 667–679. doi:10.1182/blood-2016-10-695940. ISSN 1528-0020. PMID 28028029. Check date values in: |date= (help)

Notes

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