HAEM4:Myelodysplastic Syndrome (MDS), Unclassifiable

Primary Author(s)*

Xiaolin Hu, Ph.D; Teresa Smolarek, Ph.D, FACMG

Cancer Category/Type

Myelodysplastic Syndrome (MDS)

Cancer Sub-Classification / Subtype

Myelodysplastic Syndrome, Unclassifiable (MDS-U)

Definition / Description of Disease

This subtype of MDS contains cases that can not be classified to any known categories of MDS. In 2018 WHO classification , it specified several settings:

1. Meet the criteria of any category of classifiable MDSs, but has 1% blasts detected at least two times in the peripheral blood.
2. Meet the criteria of MDS with single lineage dysplasia, MDS with ring sideroblasts and single lineage dysplasia, and MDS with isolated del(5q), but has pancytopenia (cytopenias are defined as haemoglobin concentration < 10 g/dL, platelet count < 100 x 10⁹/L, and absolute neutrophil count < 1.8 x 10⁹ /L).
3. Persistent cytopenia with < 2% blasts in the blood and <5% in the bone marrow, has MDS-defining abnormality [link to MDS cytogenetic table] but no significant dysplasia in any myeloid lineage.

However, these cases may be evolved into a specific subtype of MDS and hence need to be reclassified then.

Synonyms / Terminology

Myelodysplastic syndrome, NOS, preleukemia (obsolete); preleukaemic syndrome (obsolete)

Epidemiology / Prevalence

The incidence of MDS-U is unknown, but appears to account for a small portion of MDS cases. In a cohort of 2032 patients with MDS, the overall incidence of MDS-U was 6% .

Clinical Features

The clinical symptoms are varied but generally fall into the spectrum of MDS symptoms.

Sites of Involvement

Peripheral blood and bone marrow.

Morphologic Features

No specific morphology has been described for this disease entity. This category is a diagnosis of exclusion when no other known categories of MDS can fit.

Immunophenotype

No specific immunophenotype has been described for this disease entity. However, immunophenotyping may provide supportive evidence to clarify the blasts nature and percentage.

Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Not applicable.

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

No chromosomal abnormality is specific for this category. Common recurrent chromosomal aberrations in MDS include +8, -7, del(7q), -5, del(5q), del(20q), -Y, i(17q), t(17p), -13, del(13q), del(11q), del(12p) or t(12p), del(9q), idic(X)(q13), t(11;16)(q23;p13.3), t(3;21)(q26;q22.1), t(1;3)(p36.3;q21.2), t(2;11)(p21;q23), inv(3)(q21q26.2), t(3;3)(q21.3;q26.2), t(6;9)(p23;q34). It is noted that +8, -Y, and del(20q), are not considered diagnostic of MDS if present as sole cytogenetic aberrations.

Genomic Gain/Loss/LOH

Put your text here and/or fill in the table

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)

No specific gene mutation in this category. Common gene mutations in MDS include SF3B1, TET2, ASXL1, SRSF2, DNMT3A, RUNX1, U2AF1, TP53, EZH2, ZRSR2, STAG2, IDH1/IDH2, CBL, NRAS, BCOR.

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

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

Epigenomics (Methylation)

Genes involved in epigenetic regulation are frequently mutated in MDS such as TET2, DNMT3A, IDH1, IDH2, AXSL1, and EZH2 . These genes play a role in DNA methylation and chromatin modification as well as regulating gene expression.

Genes and Main Pathways Involved

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Diagnostic Testing Methods

• Bone marrow morphology and peripheral blood test are standard in diagnosis of MDS.
• FISH probes for MDS panel and conventional cytogenetics are also helpful in determining MDS defining cytogenetic abnormalities.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Diagnosis

2018 WHO classification defined this disease category in three specific settings as described in Definition/Description of Disease.

Prognosis

The prognosis may change as MDS-U continue to evolve into other MDS subtypes. MDS-U with 1% circulating blasts showed poor prognosis in terms of shorter over all survival and increased risk to progress to AML. MDS-U with 1% circulating blasts has a median survival of 1.8 years and 14% of these patients may progress to AML in 5 years. Patients with MDS-U with pancytopenia had a median survival of 2.7 years and 18% of these patients may progress to AML in 5 years. The prognosis of MDS-U with MDS-defining cytogenetic abnormalities is unknown .

Familial Forms

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Other Information

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Links

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References

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.

Notes

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