Myelodysplastic Syndrome - Haematology , Pathology Reference -Wintrobe , Robbins, Tejinder Singh Haematology

1. MYELODYSPLASTIC
SYNDROME
Presented by –Dr. Pritika Nehra
SMS MEDICAL COLLEGE ,
JAIPUR

2. Introduction
• complex group of myeloid disorders characterized by
 peripheral blood cytopenias
 dysplasia in bone marrow hematopoietic cellular elements
 Increased risk of development of AML
• Diagnosis is often supported by the presence of cytogenetic
alterations and, more recently, genetic mutations

3. Epidemiology And Etiology
• Disease of aging ( median age - 70 yrs ). India – 45yrs
• The incidence in U.S. - 4.1 per 1,00,000.
• Cause is not known
i) Therapy-related (t)-MDS , secondary to exposure to prior
chemo or radiation therapy
 complex karyotypes
 occur in younger patients
 different patterns of disease evolution and cytogenetic
abnormalities
 very poor prognosis

4. ii) Environmental factors
 High benzene exposure (>3 ppm)
 family history of hematopoietic cancer
 Smoking
 exposure to agricultural chemicals or solvents
Drinking wine reduced risk for all FAB types by almost
50%

5. iii) Genetic syndromes ass. with BM failure
 Ribosomopathies - Diamond-Blackfan anemia
- Schwachman-Diamond syndrome
- Dyskeratosis congenita
- Cartilage hair hypoplasia
- Treacher Collins syndrome
 Patients with Fanconi anemia are also at increased risk of
developing MDS (Runx1 mutation)

6.  Rare familial syndromes
• Younger patients with thrombocytopenia or MDS should
be screened for Runx1 mutations
• Germline mutations in GATA-2 have also been involved in
a familial syndrome of MDS/AML, MonoMAC, and
lymphedema
• MonoMAC is an autosomal dominant syndrome associated
with monocytopenia; B and NK cell lymphopenia; and
mycobacterial, fungal, and viral infections, also associated
with pulmonary alveolar proteinosis

7. PATHOGENESIS

8.  MDS : a stem cell disorder
• malignant transformation of myeloid stem cell
• clones derived from an abnormal stem cell
 Apoptosis in MDS
• increased apoptosis of haemopoietic precursors
• Presence of cytopenias despite a typically hypercellular
bone marrow.
• For those patients undergoing leukaemic transformation,
the cytopenias arise due to maturation block of the
malignant cells
• more prominent in early MDS, such as RA and RARS, than
in advanced MDS with excess myeloblasts

9. Ineffective Hematopoiesis
• Colony forming capacities of pleuripotent stem cells and
their progeny are low or absent
• Lower level of GM-CSF, M-CSF,IL 6 .IL 3
• CFU- GM less responsive to both G-CSF & GM-CSF
• More dramatic in pts with RAEB or RAEB –t
Angiogenesis
• Autocrine production of angiogenic molecules promotes
expansion of leukemic clone
• Vascular endothelial growth factor(VEGF) and its receptor
VEGFR-1 And VEGFR-2 is overexpressed

10. Immunological abnormalities in MDS
• Commonly encountered in MDS
• T-cell expansion
• B- cell alteration
• Particularly in cases of hypoplastic MDS
• • Acquired mutations in the PIG-A gene characteristic
of paroxysmal nocturnal haemoglobinuria (PNH) are
also encountered

11. Molecular Pathogenesis
The most frequent events are genes involved in control of
gene splicing and epigenetic regulators such as TET2or
ASXL1 or EZH2.
• TET2
 located on chromosome 4q24
 DNA hydroxymethylation
 mutations in TET2 -abnormal DNA methylation patterns
that could broadly impact gene expression patterns in
MDS
 role in the homeostasis of hematopoietic stem cells
 associated with response to azacitidine

12. • EZH2
 located on chromosome 7 , Polycomb group family
 control of epigenetic gene repression
 EZH2 mutations in MDS inactivate the gene
 poor prognosis
• specific molecular pathways may separate different subsets
of patients
• Bejar et al. separated pts into 2 major subgroups: those
with p53 mutations and complex cytogenetics, and those
without p53 mutations
Aberrant DNA Methylation Of Promoter Cpg Islands-
 common both in AML and MDS
 use of hypomethylating agents in MDS
 patients with higher methylation scores had worse survival

13. Clinical Presentation & Complications
• not specific.
• Mostly diagnosed after peripheral blood examination
• suspected based on presence of one or more cytopenias
• symptoms of anemia, thrombocytopenia, fever, other
constitutional symptoms, or unexplained infections
• thorough evaluation to rule out other conditions that may
exclude MDS diagnosis
• diagnostic test always includes evaluation of the
morphology of a bone marrow specimen
• Cause of death - MDS-related with the most common
events being infection (38%), transformation to AML
(15%), and haemorrhage (13%

14. Diagnostic Evaluation
• Based on presence of dysplastic features on BM aspirate
Recommended -500 BM cells and 200 PBF cells
Dysplasia >10% of cells for each specific lineage
 Erythroid dysplasia -sideroblasts,cellular vacuolization
 Dysgranulopoiesis -alterations in size, nuclear
hypolobation, or hypersegmentation
 Dysmegakaryopoiesis -micromegakaryocytes, hypolobation
or multinucleation
• Examination of a BM biopsy helps in evaluating cellularity
and the presence of significant fibrosis, making a diagnosis
of hypoplastic MDS versus aplastic anemia

15. Evolution of MDS Classification

16. FAB classification in 1983
Five entities were defined:
• Refractory anemia (RA)
• RA with ringed sideroblasts (RARS)
• RA with excess blasts (RAEB)
• RA with excess blasts in transformation (RAEB-t)
• Chronic myelomonocytic leukemia (CMML)

17. DIFFERENCES BETWEEN WHO AND FAB
• The WHO uses cytogenetic findings.
• RAEB-t was eliminated as it got included within
AML(>20%blasts).
• criteria proposed by the WHO replaced the prior FAB 30%
blasts criteria,decreased to 20% by WHO
• CMML was removed and put in a new category of
myelodysplastic/myeloproliferative diseases.
• Adds the subtypes 5q syndrome and unclassifiable MDS.
• Recognizes the prognostic importance of % of bone
marrow blasts

20. • The most important assay,mandatory , is cytogenetic
analysis. There is no specific cytogenetic pattern diagnostic
of MDS
• both a diagnostic and a prognostic value
• In patients with profound marrow hypocellularity, the
presence of a cytogenetic alteration will differentiate
hypoplastic MDS from aplastic anemia
• Recent 5-subgroup classification , forms basis of IPSS-R

21.  Flow cytometry can help in the confirmation of MDS, and
specific phenotypes may have prognostic value.
• Presently , no panel diagnostic of MDS, can’t replace
morphologic examination
• may try to quantitate the percentage of blasts by
annotating the number of CD34+ cells.
• not an appropriate tool to estimate % of blasts, only
complementary
 Newer genomic technologies are currently being
developed that allow the analysis of multiple genetic events
in MDS and other cancers.
• These include next-generation gene sequencing and
analysis of single nucleotide polymorphisms, not currently
integrated into clinical practice

22. MDS-Related Syndromes: CMML and
Overlap Myelodysplastic Myeloproliferative Syndromes
• Chronic myelomonocytic leukemia - distinct WHO entity
• also includes BCR/ABL negative CML, MDS/MPN
unclassified, juvenile myelomonocytic leukemia, and
potentially refractory anemia with ring sideroblasts and
thrombocytosis (RARS-T).
• Traditionally, CMML - subtype of MDS. IPSS - patients
with CMML if the white cell count was less than 12 ×
103/L
• The natural history of patients with CMML is distinct from
that of patients with classic MDS. Patients tend to have
higher frequency of B symptoms and extramedullary
manifestations of the disease. Tissue infiltration causing
hepatic or renal dysfunction is not uncommon.

23. • Diagnosis –
 Persistent monocytosis (>1 × 109/L) without evidence of
BCR/ABL fusion genes or PDGFR alterations.
 Blasts(promonocytes) < 20% and
 dysplasia is routine, less pronounced than MDS categories
• CMML-1 and CMML-2 , based on the percentage of bone
marrow and peripheral blood blasts (CMML-1 < 10% bone
marrow blasts or < 5% in peripheral blood; CMML-2 with
more blasts)
• markers of myelomonocytic differentiation - CD33 and CD13
• Cytogenetic alterations occur as in other cases of MDS
• presence of RAS mutations - 40% of patients.
MDS/MPN unclassified (MDS/MPN-U) disorders - advent of
agents that inhibit JAK2, a common molecular alteration in
MPN that may explain the proliferative feature of the disease

24. Approach to MDS

25. PHYSICAL EXAMINATION
• Anemia
• 20% of pts have splenomegaly
• Unusual skin lesions –
Sweet syndrome, Granulocytic Sarcoma
• Autoimmune abnormalities (uncommon) - Seen in 14 % of
the patients. Most common is cutaneous vasculitis.
HISTORY –
• Family history
• Exposure to Radiotherapy , Chemotherapy
• Recurrent Infections , Bleeding Gums

26. • Stereotypical anomalies point to a constitutional syndrome
 Short stature, abnormal thumbs - Fanconi anemia
 Early graying - Telomeropathies
 Cutaneous warts -GATA2 deficiency
LABORATORY STUDY
CBC
• Threshold for cytopenia (IPSS)
 Hb < 10 g/dl
 Absolute neutrophil count< 1.8x 109 /L
 Platelets < 100 x 10 9/L
• Anemia (MC),alone or as part of bi/pancytopenia
• Isolated neutropenia or thrombocytopenia is more unusual.

27. PBF
• RBCs - macrocytic
• Platelets - large and lack granules.
• Neutrophils - hypo granulated; hypo segmented, ringed, or
abnormally segmented nuclei; contain Döhle bodies; and
may be functionally deficient
• Circulating myeloblasts usually correlate with marrow blast
 BONE MARROW
• Usually normal or hypercellular
• 20% of cases : hypocellular to be confused with AA.
• No single characteristic feature of marrow morphology
distinguishes MDS, but the following are commonly
observed:

34. DIFFERENTIAL DIAGNOSIS
• Vitamin B12 or folate deficiency
• Vitamin B6 deficiency - Can be assessed by a therapeutic
trial of pyridoxine if the bone marrow shows ringed
sideroblast
• AML - WHO considers the presence of 20% blasts in the
marrow as the criterion that separates AML from MDS
• Reactive Causes of Dysplasia –
HIV , recent cytotoxic therapy, alcoholism , recurrent
infections
• Congenital Sideroblastic Anaemia
• Paroxysmal Nocturnal Haemoglobinuria
• Toxins (lead & benzene) and Drugs ( Isoniazid )

36. Risk Stratification