Bone marrow neoplastic

• De novo presentation
• MDS / MPN, NOS shows simultaneous presence of both myelodysplastic (cytopenias) and myeloproliferative (cytosis) features
• Diagnostic criteria for MDS / MPN, NOS include cytopenias with thresholds aligned with myelodysplastic syndromes (MDS): hemoglobin < 13 g/dL (men) or < 12 g/dL (women), absolute neutrophil count < 1.8 x 10⁹/L or platelet count < 100 x 10⁹/L
  • Myeloproliferative features include thrombocytosis (platelet count ≥ 450 x 10⁹/L) or leukocytosis (white blood cell count ≥ 13 x 10⁹/L)
  • Blast percentage in peripheral blood or bone marrow must be < 20%, as specified by both WHO and ICC classifications
• Diagnosis is based on exclusion of
  • Other defined myeloid neoplasms
  • Other MDS / MPN entities
  • Cases of MDS or MPN that transform to MDS / MPN-like
  • Absence of biallelic TP53 mutations
  • No t(3;3), inv(3) or del5q (ICC)
• No specific cytogenetic / molecular abnormality defines MDS / MPN, NOS
• Intrinsic risk of developing into acute myeloid leukemia

• Clonal hematopoietic stem cell origin (Indian J Hematol Blood Transfus 2019;35:3)
• General nonspecific heterogeneous myeloid mutations drive the disease (WHO 5th edition)
  • Common mutations include TET2, NRAS, RUNX1, CBL, SETBP1 and ASXL1 (Leukemia 2013;27:1852)
  • Genetic mutations in genes related to RNA splicing (e.g., SRSF2), epigenetic regulation (e.g., ASXL1, DNMT3A), transcription factors (e.g., RUNX1) and signaling pathways (e.g., RAS) (Hematology Am Soc Hematol Educ Program 2011;2011:264, Annu Rev Pathol 2013;8:21)
  • SETBP1 mutations have been identified in up to 10% of cases and could aid in supporting the diagnosis (Leukemia 2013;27:1852)
  • TET2 mutation is seen in ~30% of cases
  • Double gene mutations are possible; however, comutation of 3 and more genes is extremely rare (Leuk Res Rep 2020;14:100229)
• Palomo et al. has shown subgroups with distinct molecular signatures / subtypes in up to 60% of cases (Blood 2020;136:1851, Int J Hematol 2015;101:229)
  • Chronic myelomonocytic leukemia (CMML)-like (17%), atypical chronic myeloid leukemia (aCML)-like / MDS / MPN with neutrophilia-like (33%), MDS / MPN-RS-T-like (11%), TP53 positive (13%) and others
  • Molecular subgroups correlate with corresponding hematologic phenotypes and outcomes
  • Increased SRSF2 / SETBP1 double mutant pattern noted in MDS / MPN with i(17q)
• MDS with del(5q) can be associated with JAK2 p.V617F (WHO 5th edition) (Mod Pathol 2022;35:470)
  • It is recommended that cases with combined del(5q) and JAK2 p.V617F mutation be classified as MDS with isolated del(5q) rather than MDS / MPN, NOS
• Provisional entity: MDS / MPN with isolated isochromosome (17q), classified under MDS / MPN, NOS category according to the International Consensus Classification (ICC)
  • Requires the presence of isochromosome (17q), either as an isolated abnormality or accompanied by one additional cytogenetic abnormality excluding monosomy 7 or (7q) deletion
  • Deletion of 17p (leading to monoallelic TP53 loss without multihit or biallelic inactivation) and duplication of 17q
  • Common mutations include SRSF2, SETBP1, ASXL1 and NRAS, with frequent co-occurrence of SRSF2 and SETBP1
  • Partial overlap with aCML (e.g., SETBP1 / ASXL1) and to a lesser content, CMML (e.g., SRSF2 / NRAS) but distinguished by the defining cytogenetic change and the absence of multihit TP53 alterations (Virchows Arch 2023;482:69)

Mutations and the pathways that were found in MDS / MPN, NOS (Int J Hematol 2015;101:229, Leukemia 2020;34:656, Mod Pathol 2022;35:470, Mod Pathol 2022;35:705)

Signaling (most common)		Epigenetic regulators		Transcription factors	RNA splicing
Receptors	Signal transduction molecule	DNA methylation	Histone modifications
NRAS FLT3 CSF3R	CBL SETBP1	DNMT3A TET2 IDH1/2	ASXL1 EZH2 SUZ12 EED	RUNX1 CEBPA NPM1 WT1 TP53	SRSF2 SF3B1 U2AF1

Diagnostic criteria for myelodysplastic / myeloproliferative neoplasm (MDS / MPN), NOS (WHO 5th edition) (Leukemia 2022;36:1703)

• Peripheral blood: evidence of both cytopenias and proliferative features (see Essential features for specific thresholds)
• Bone marrow examination: dysplastic changes in hematopoietic cells and signs of proliferation
• Genetic testing on blood or bone marrow: mutations typical of both dysplastic and proliferative myeloid neoplasms
• Exclusion required for secondary myeloid neoplasms due to prior therapy, specific gene rearrangements (e.g., BCR::ABL1 or those involving PDGFRA, PDGFRB, JAK2 or FGFR1), cases with biallelic TP53 alterations and other defined MDS / MPN subtypes
• Certain MDS cases may progress to resemble MDS / MPN, NOS through development of proliferative characteristics

Diagnostic criteria for myelodysplastic / myeloproliferative neoplasm (MDS / MPN), NOS (ICC) (Blood 2022;140:1200)

• Myeloid disorder exhibiting combined proliferative and dysplastic traits that does not align with criteria for any other specific myeloid neoplasms per WHO
• Cytopenia (meeting MDS thresholds as defined in Essential features)
• Blast cells accounting for < 20% in both blood and bone marrow
• Elevated platelets (≥ 450 x 10⁹/L) or white blood cells (≥ 13 x 10⁹/L)
• Confirmation of clonality through cytogenetic changes or somatic mutations
• If clonality is not demonstrable, persistent findings over time with ruled out alternative causes (e.g., prior cytotoxic exposure or other etiologies mimicking the overlap features)
• Absence of BCR::ABL1 fusion or genetic changes linked to myeloid / lymphoid neoplasms with eosinophilia and tyrosine kinase fusions; no t(3;3)(q21.3;q26.2), inv(3)(q21.3;q26.2) or isolated del(5q)
• Subtype inclusion: MDS / MPN with isolated i(17q) as a specific variant

Proposed criteria for MDS / MPN with isolated isochromosome (17q) (Mod Pathol 2022;35:705)

• Myeloid disorder presenting with both proliferative and dysplastic characteristics from onset, not qualifying for any other MDS / MPN, MDS or MPN subtype per WHO
• Blast proportion under 20% in peripheral blood and bone marrow
• Dysplastic elements akin to MDS, paired with proliferative signs such as platelets ≥ 450 x 10⁹/L with megakaryocytic hyperplasia in bone marrow or white blood cells ≥ 13 x 10⁹/L
• Cytogenetics showing isolated i(17q) or i(17q) plus one other abnormality [not including del(7q) or -7]
• No fusions involving BCR::ABL1, PDGFRA, PDGFRB, FGFR1 or PCM1::JAK2
• Lack of typical MPN driver mutations (e.g., in JAK2, CALR or MPL)
• No recent exposure to cytotoxic agents or growth factor therapy that could account for the myelodysplastic / myeloproliferative features

• Bone marrow (Front Oncol 2021;11:778741)
  • Hypercellular or hypocellular
    • Hypercellular with myeloid lineage predominance
  • Dysplasia is seen in at least one hematopoietic lineage
  • Percentage of blasts in peripheral blood and bone marrow must be < 20%
    • Typically few blasts are seen
    • Include promonocytes as blast equivalents
  • Bone marrow fibrosis is seen in up to 30%
  • Increased megakaryocytes with variable clustering
    • Often myelodysplasia-like with small size and nuclear hypolobation
    • MDS / MPN with iso(17q) typically shows the myelodysplasia-like megakaryocytes
  • Transformations of either MDS or MPN should not be included within MDS / MPN categories

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

A 65 year old man presents with fatigue and thrombocytosis. Bone marrow biopsy reveals atypical megakaryocytes and dysplastic erythroid elements. No ring sideroblasts are identified. Cytogenetic analysis shows no BCR::ABL1 fusion, PDGFRA / PDGFRB rearrangement or del(5q). Flow cytometry revealed rare blasts (1%) with no aberrant immunophenotypic expression. Based on WHO criteria for MDS / MPN, NOS, which of the following findings would confirm the diagnosis?

1. Increased lactate dehydrogenase (LDH)
2. Peripheral blood monocyte count > 1 x 10⁹/L
3. Presence of SETBP1 mutations
4. Ring sideroblasts with thrombocytosis

C. Presence of SETBP1 mutations. MDS / MPN, NOS is characterized by overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms but lacks specific criteria for other subtypes. SETBP1 mutation is seen in 10% of MDS / MPN, NOS patients and is generally the most specific marker seen in  MDS / MPN, NOS. Answer B is incorrect because it is a diagnostic criterion for chronic myelomonocytic leukemia (CMML), a distinct MDS / MPN subtype. The patient's presentation lacks monocytosis, making this irrelevant. Answer D is incorrect because ring sideroblasts and thrombocytosis define MDS / MPN-RS-T, a separate entity. This patient's thrombocytosis and dysplasia without ring sideroblasts align with MDS / MPN, NOS, not MDS / MPN-RS-T. Answer A is incorrect because elevated LDH reflects tumor burden but does not confirm the diagnosis.

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Reference: MDS / MPN, NOS (unclassifiable)