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
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
