Bone marrow neoplastic

• Myelodysplastic syndrome with single lineage dysplasia (MDS SLD) is defined as persistent unexplained cytopenias (anemia [most common], neutropenia or thrombocytopenia) or bicytopenia with ≥ 10% dysplastic cells in 1 myeloid lineage

Contributed by Karan Saluja, M.D. and Beenu Thakral, M.D.

• Prognosis in MDS is determined using IPSS-R diagnostic scoring system, which takes into account cytogenetic findings, bone marrow blast percentage, hemoglobin, platelet count and absolute neutrophil count (ANC)
• 5 risk groups:
  • Very low risk: ≤ 1.5
  • Low: > 1.5 - 3.0
  • Intermediate: > 3.0 - 4.5
  • High: > 4.5 - 6.0
  • Very high: > 6.0
• References: Blood 2012;120:2454, J Natl Compr Canc Netw 2015;13:261

IPPS-R scoring for MDS

Prognostic variables	Score value
	0	0.5	1.0	1.5	2.0	3.0	4.0
Karyotype	Very good	-	Good	-	Intermediate	Poor	Very poor
Percentage of bone marrow blasts	≤ 2%	-	> 2% to < 5%	-	5 - 10%	> 10%	-
Hemoglobin (Hb) (g/dL)	≥ 10	-	8 to < 10	< 8	-	-	-
Platelets (x109/L)	≥ 100	50 to < 100	< 50	-	-	-	-
Absolute neutrophil count (ANC) (x109/L)	≥ 0.8	< 0.8	-	-	-	-	-
Cytogenetic prognostic group: Very good: loss of Y and del(11q) Good: normal, del(5q), del(12p), del(20q), double, including del(5q) Intermediate: del(7q), gain of chromosome 8, 19, i17q, ≥ 2 independent noncomplex clones Poor: loss of chromosome 7, inv3, t(3q), del(3q), double, including loss of chromosome 7 or del(7q), complex (3 abnormalities) Very poor: complex (> 3 abnormalities)

• Morphologic features of dysplasia in erythroid, myeloid or megakaryocytic lineages

Dyserythropoiesis	Dysgranulopoiesis	Dysmegakaryopoiesis
Nuclear budding or multinucleation	Small or unusually large size granulocytes	Micromegakaryocytes
Internuclear bridging	Nuclear hyposegmentation (pseudo Pelger-Huët)	Nuclear hypolobation
Karyorrhexis	Nuclear hypersegmentation	Multinucleation or widely separated nuclear lobes
Megaloblastoid changes	Hypogranularity; agranularity
Presence of ring sideroblasts	Pseudo Chediak-Higashi granules
Cytoplasmic vacoulization	Auer rod

Contributed by Beenu Thakral, M.D.

Contributed by Beenu Thakral, M.D.

• Cytogenetics findings (J Clin Oncol 2012;30:820):
  • Conventional karyotyping should be performed in all MDS cases at diagnosis, as it defines prognosis
  • Cytogenetic abnormalities are seen in 50 - 60% of MDS; these abnormalities usually include del20q, gain in chromosome 8 or abnormalities in chromosome 5 and 7
  • MDS SLD with isolated thrombocytopenia, the presence of cytogenetic or molecular abnormality is helpful in distinguishing MDS from immune mediated thrombocytopenia

MDS defining cytogenetic abnormalities

Unbalanced cytogenetic abnormalities del(5q) or t(5q) i(17q) or t(17p) -13 or del(13q) del(11q) del12p or t(12p) del(9q) idic(X)(q13)

Balanced cytogenetic abnormalities t(11;16)(q23; p13.3) t(3;21)(q26.2;q22.1) t(1;3)(p36.3;q21.2) t(2;11)(p21;q23) inv(3)(q21q26.2)/t(3;3)(q21q26.2) t(6;9)(p23;q34)

• Molecular findings (Int J Lab Hematol 2020;42:671, Blood 2012;119:3578, Leuk Res 2015;39:6):
  • Recurrent somatic mutations are identified in 80 - 90% of MDS cases
  • Most commonly mutated genes in MDS include RNA splicing (SF3B1, SRSF2, U2AF1 and ZRSR2) or epigenetic regulation of gene expression via DNA methylation (TET2, DNMT3A, IDH1 and IDH2) or genes involved in histone modification (ASXL1 and EZH2)
  • Specific mutations associated with morphologic features and MDS include SF3B1 mutation with ring sideroblasts and mutations in ASXL1, RUNX1, TP53 and SRSF2 are associated with severe granulocytic dysplasia
  • Acquired clonal mutations identical to those seen in MDS (TET2, DNMT3A, SF3B1, ASXL1 and JAK2) can also occur in hematopoietic cells of apparently healthy older individuals without MDS; thus, the presence of MDS associated somatic mutations alone are not considered diagnostic of MDS even in patients with unexplained cytopenia

Genes commonly mutated in MDS

	Pathway	Frequency	Prognosis
SF3B1	RNA splicing	20 - 30%	Favorable
TET2	DNA methylation	20 - 30%	Neutral
ASXL1	Histone modification	15 - 20%	Adverse
SRSF2	RNA splicing	15%	Adverse
DNMT3A	DNA methylation	10%	Adverse
RUNX1	Transcription factor	10%	Adverse
U2AF1	RNA splicing	5 - 10%	Adverse
TP53	Tumor suppressor	5 - 10%	Adverse
EZH2	Histone modification	5 - 10%	Adverse
ZRSF2	RNA splicing	5 - 10%	Neutral
STAG2	Cohesion complex	5 - 7%	Adverse
IDH1 / IDH2	DNA methylation	5%	Neutral
CBL	Signaling	5%	Adverse
NRAS	Transcription factor	5%	Adverse
BCOR	Transcription factor	5%	Adverse

Characteristics of ICUS, CHIP / ARCH, CCUS and MDS

	Idiopathic cytopenia of uncertain significance (ICUS)	Clonal hematopoiesis of indeterminate potential or age related clonal hematopoiesis (CHIP / ARCH)	Clonal cytopenia of uncertain significance (CCUS)	Myelodysplastic syndrome (MDS)
Clonality	-	+	+	+
Cytopenia	+	-	+	+
Dysplasia	-	-	-	+
Bone marrow blasts	< 5%	< 5%	< 5%	< 20%
Cytogenetic abnormality	No	No	Can be seen but not MDS defining	Present in 50 - 60% of cases, can be MDS defining
Typical number of mutated genes	0	1	1.5 - 2	2.6 - 17
Commonly mutated genes	NA	DNMT3A, TET2, ASXL1 (DTA) genes	DNMT3A, TET2, ASXL1, SRSF2, TP53 or U2AF1	SF3B1, SRSF2, U2AF1, TET2, DNMT3A, ASXL1, EZH2, IDH1, IDH2, BCOR, BCORL1, RUNX1, TP53, PHF6, NRAS, KRAS
Typical VAF (variants with allele frequency)	NA	2 - 10%	20 - 30%	> 30%
Risk of developing MDS or acute myeloid leukemia	Very low	Low	High	NA

• MDS with ring sideroblasts and single lineage dysplasia:
  • Characterized by unilineage dysplasia and distinguished from MDS SLD by presence of ≥ 15% ring sideroblasts or ≥ 5% ring sideroblasts, if SF3B1 mutation is present
• MDS unclassifiable:
  • Cases with single lineage dysplasia in presence of 1% blasts in peripheral blood on 2 separate occasions or by presence of pancytopenia
• Nonclonal causes of dysplasia:
  • Drugs, medications and toxin exposure
  • Growth factor therapy
  • Viral infection
  • Immunological disorders
  • Vitamin deficiencies: B12, folate (Clin Lymphoma Myeloma Leuk 2014;14:e141)
  • Copper deficiency or zinc excess (Pathology 2014;46:246)
• References: Am Soc Clin Oncol Educ Book 2019;39:400, Am J Clin Pathol 2019;152:347, Eur J Haematol 2021;106:500, Blood Adv 2021;5:2272

A 50 year old man presented with macrocytic anemia with no known medical history. Serum vitamin B12 and folate levels are normal. A bone marrow biopsy shows hypercellular (80%) bone marrow with erythroid predominance, dyserythropoiesis and 10% ring sideroblasts with 2% blasts on aspirate smears. Peripheral blood smear review shows macrocytic anemia and no circulating blasts. Cytogenetics shows a diploid karyotype. Next generation sequencing identified mutation in the U2AF1 gene. According to the current WHO 2016 revised classification, how should this case of MDS be classified?

1. Myelodysplastic syndrome, unclassifiable
2. Myelodysplastic syndrome with del5q
3. Myelodysplastic syndrome with ring sideroblasts
4. Myelodysplastic syndrome with single lineage dysplasia

D. Myelodysplastic syndrome with single lineage dysplasia

Comment Here

Reference: MDS with single lineage dysplasia

Which of the following RNA splicing gene is commonly mutated in MDS?

1. ASXL1
2. RUNX1
3. SF3B1
4. STAG2
5. TP53

C. SF3B1

Comment Here

Reference: MDS with single lineage dysplasia