Myelodysplastic syndrome

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 i nfection (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

18. 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

19. 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

20. 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.

21. 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

22. Approach to MDS

23. 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

24. 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< 1.8 x 109 /L Platelets < 100 x 10 9/L Anemia (MC),alone or as part of bi/ pancytopenia • Isolated neutropenia or thrombocytopenia is more unusual.

25. 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:

26. 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 )

27. Risk Stratification