Myelodysplastic syndrome
- 1. Myelodysplastic Syndromes Malvika tripathi Resident of Pathology
- 2. • They represent a spectrum of stem cell malignancies that are characterized by – 1. Ineffective hematopoiesis 2. Cytopenias, 3. Qualitative disorders of blood cells and their precursors, 4. Clonal chromosomal abnormalities, & 5. A variable predilection to undergo evolution to acute myelogenous leukemia (AML). • The somatic mutations leading to these disorders arise in a multipotential hematopoietic cell. • Uncommon before 50 years of age (median age - 65). • M>F.
- 3. History • 1938 – Rhoades and Barker – Refractory anemia. • 1949 – Hamilton and Paterson – Preleukemic anemia. • 1953 – Block et al. – Preleukemia. • 1956 – Bjorkman – Refractory anemia with ring sideroblasts. • 1974 - Miescher and Farguet - CMML. • 1982 - Bennett et al. – Myelodysplastic syndromes.
- 10. Pathogenesis • These disorders arise from the clonal expansion of a multipotential hematopoietic cell. • Chromosome abnormalities may not be present in lymphoid populations. • T-cell receptor analysis and X chromosome inactivation analysis indicate that marrow and, to a lesser extent, blood T cells, natural killer (NK), and B cells are part of the malignant clone in at least 50%of patients. • Molecular genetic studies of patient's cells show identifiable gene mutations in approximately 60% of patients.
- 11. • Mutations in RAS(codon 12), FMS (codon 969) and p53. • Hypermethylation of p15(inhibitor of CDK 4 & 6) - 1/3rd cases. • The specific characteristics of ineffective erythropoiesis and granulopoiesis include a decreased proportion of cells in the DNA synthesis phase of the mitotic cycle and a marked increase in the fraction of late precursor cells undergoing apoptosis. • Increased levels of apoptotic mediators are present in cells, including tumor necrosis factor (TNF)-, FAS antigen (CD95), and calcium-dependent nuclease activity. • The apoptosis of erythroid precursors may involve BCL-2 related proteins and downstream of FAS. • Mild shortening of cell life span also contributes to the cytopenias.
- 12. Clinical features • Asymptomatic or can have pallor, weakness, loss of a sense of well being, and exertional dyspnoea (Severe anemia). • Infections related to severe neutropenia or neutrophil dysfunction. • Hemorrhage related to severe thrombocytopenia or platelet dysfunction at the time of diagnosis. • Rarely, patients have fever unrelated to infection. • Arthralgia is the initial complaint in some patients. • Hepatomegaly or splenomegaly occurs in approximately 5 or 10% of patients, respectively.
- 13. • Cutaneous manifestations – 1. Sweet syndrome : - • Erythematous patches on the arms, face, and legs that progress to painful brown plaques. • The plaques may ulcerate and produce large necrotizing skin lesions. • Occurs in middle-aged women, lasts for 6 to 10 weeks, often is associated with blood neutrophilia, and may recur. • At least 10% of patients with Sweet disease develop AML 2. Granulocytic sarcoma 3. Erythema nodosum 4. Vegetative pyoderma gangrenosum 5. Langerhans cell histiocytosis
- 14. • Para neoplastic autoimmune complications 1. Cutaneous vasculitis, 2. Monoarticular arthritis, 3. Pericarditis, 4. Pleural effusion, 5. Myositis, 6. Skin ulceration, 7. Peripheral neuropathy, 8. Polychondritis, 9. Polymyalgia rheumatica, 10. Raynaud's disease, 11. Sjogrens syndrome, 12. IBD. • Ocular complications 1. Corneal ulcers, 2. Iridocyclitis, 3. Vitreous haemorrhage, 4. Retinal haemorrhage, 5. Optic neuritis.
- 15. Investigations 1. Peripheral blood smear examination 2. Bone marrow aspiration 3. Cytochemical stains and Immunocytochemistry 4. Trephine biopsy 5. Cell culture 6. Cytogenetics 7. Flow cytometry
- 16. PS & Bone marrow findings
- 29. • Since the findings of peripheral smear like basophilic stippling , Howell jolly bodies etc. are not diagnostic of MDS, potentially contributing conditions must be excluded. • Nutritional status, alcohol and drug abuse, occupational exposure to toxic chemicals, prior treatment with antineoplastic or radiotherapy and risk factors for HIV infection should be elicited. • The preponderance of macrocytic anemia in MDS necessitates exclusion of Vitamin B12 and folate deficiency.
- 30. Trephine biopsy • Trephine biopsy in MDS is particularly useful to determine cellularity of marrow, Abnormal localization of immature precursors(ALIP), Reticulin fibrosis, megakaryocytic dysplasia & Lymphoid nodules. • Bone marrow is either Hyper/ Normo cellular. • There is increase in number of early normoblasts and proerythroblasts. • Late normoblasts are reduced. • Megaloblasts have regular & uniform nuclei with linear nucleoli.
- 31. • There is preponderance of promyelocytes and myelocytes in the marrow. • Blast cells are increased. • Blasts are normally present in the Para trabecular region of the marrow but if they are dislocated to the central region of the marrow then this is known as Abnormal localization of immature precursors (ALIP). • There is presence of aggregates (3-5 cells) or clusters (>5 cells) of blasts in the central portion of the marrow. • ALIP is the indicator for increased risk of transformation to AML and is associated with poor prognosis.
- 32. • Megakaryocytes are increased in number and there is change in topography and many are seen in para trabecular location. • Micromegakaryocytes are characteristic and in cases of doubt CD41/CD61 can be used to confirm. • Myelofibrosis, an abnormal increase in the number & thickness of Reticulin fibres in the bone marrow may be detected by a silver impregnation stain. • Myelofibrosis may be detected in any variant but is more commonly related with therapy related MDS. • Absence of splenomegaly and rapid progressive course distinguishes it from idiopathic myelofibrosis.
- 33. • The diagnosis of MDS may be enhanced by the application of cytochemical stains and immunophenotyping studies. • The former include iron stains for identification of ringed sideroblasts and PAS-reactive erythroblasts to assess dyserythropoiesis. • Peroxidase or Sudan black B to confirms the myeloid lineage of blasts and nonspecific or double esterase stains to discern abnormal granulocyte and monocyte forms. Cytochemical stains and Immunocytochemistry
- 34. • Immunocytochemistry may be necessary to exclude a lymphoid origin of primitive blasts, whereas erythroid precursors may be distinguished by a glycophorin-A- reactive antibody; myeloid progenitors may be quantified using antibodies to CD13,CD14 and CD33. • Dysplastic or immature megakaryocytes may be detected by antibodies with specificity for factors VIII or CD41 or the HPI-ID monoclonal antibody.
- 35. Cell culture • Clonal growth of marrow progenitors in soft agar or other viscous culture systems usually is abnormal in patients with clonal hemopathies. • Colony-forming units for granulocytes and monocytes (CFU-GM) are decreased. • Very small colonies or clusters with impaired maturation often dominate the cultures. • Circulating monocyte colony-stimulating factor (M-CSF) is increased in some patients with MDS.
- 36. Cytogenetics Cytogenetic abnormalities in MDS Interstitial or terminal deletion del 5q, del 7q, del 11q, del 20q, del 20p Chromosome deletion del 7, del Y, del 17 Chromosomal duplication Trisomy 8, 11,21 Translocations t(3;3)(q21;q26) t(1;7)(p11;p11) Isochromosome iso 17q Complex pattern
- 37. Prognosis
- 39. International prognosis scoring system Risk groups: Low, 0; INT-1, 0.5–1.0; INT-2, 1.5–2.0; High, ≥2.5. Karyotype: Good score, -Y, del(5q); poor score, complex abnormalities and chromosome 7 abnormalities; intermediate score, other abnormalities
- 42. References
- 43. Thank You