Myeloproliferative neoplasm, NOS
Haematolymphoid Tumours (WHO Classification, 5th ed.)
 | This page is under construction |
editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Myeloproliferative Neoplasm (MPN), Unclassifiable.
(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)
Primary Author(s)*
Thomas Lee, MD, PhD, University of California, Los Angeles
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | Myeloid proliferations and neoplasms |
| Family | Myeloproliferative neoplasms |
| Type | Myeloproliferative neoplasms |
| Subtype(s) | Myeloproliferative neoplasm, NOS |
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
Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)
| Signs and Symptoms | EXAMPLE: Asymptomatic (incidental finding on complete blood counts)
EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon) |
| Laboratory Findings | EXAMPLE: Cytopenias
EXAMPLE: Lymphocytosis (low level) |
editv4:Clinical FeaturesThe content below was from the old template. Please incorporate above.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
Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)
| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE: CD1 |
| Positive (subset) | EXAMPLE: CD2 |
| Negative (universal) | EXAMPLE: CD3 |
| Negative (subset) | EXAMPLE: CD4 |
editv4:ImmunophenotypeThe content below was from the old template. Please incorporate above.There is no defining immunophenotype.
Chromosomal Rearrangements (Gene Fusions)
Put your text here and fill in the table
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: 3'ABL1 / 5'BCR | EXAMPLE: der(22) | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add reference) |
Yes | No | Yes | EXAMPLE:
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.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].
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).Please incorporate this section into the relevant tables found in:
- Chromosomal Rearrangements (Gene Fusions)
- Individual Region Genomic Gain/Loss/LOH
- Characteristic Chromosomal Patterns
- Gene Mutations (SNV/INDEL)
Follow-up studies on a 6 - 12 month interval can provide additional information for classification[1].
Individual Region Genomic Gain / Loss / LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.)
| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7:1- 159,335,973 [hg38] |
EXAMPLE:
chr7 |
Yes | Yes | No | EXAMPLE:
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8:1-145,138,636 [hg38] |
EXAMPLE:
chr8 |
No | No | No | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add reference). |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.There are no characteristic genomic gain/loss/LOH.
Characteristic Chromosomal Patterns
Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.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].
Gene Mutations (SNV / INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.)
| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.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
Epigenomic Alterations
Put your text here
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.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].
Genetic 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.
Familial Forms
Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)
Additional Information
Put your text here
Links
Put your links here (use link icon at top of page)
References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)
- ↑ 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.
- ↑ 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) - ↑ 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) - ↑ 4.0 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). - ↑ 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.
- ↑ 6.0 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.
- ↑ 7.0 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.
- ↑ 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) - ↑ 9.0 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) - ↑ 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
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. *Citation of this Page: “Myeloproliferative neoplasm, NOS”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Myeloproliferative_neoplasm,_NOS.