General Overview of MDS Flashcards
Definition of MDS ?
- clonal hematopoietic stem cell disease characterized by:
- cytopenias
- in at least one lineage
- dysplasia in one or more of the major myeloid lineages
- ineffective hematopoiesis
- recurrent genetic abnormalities
- increased risk of developing AML
- cytopenias
What are the recommended thresholds
for cytopenias in MDS ?
- hemoglobin <10 g/dL
- platelet count <100 X10^9/L
- absolute neutrophil count <1.8 x19^9/L
- however, can have higher numbers on CBC as long as there is definitive morphologic or cytogenetic findings present
Which specific MDS categories
can have associated thrombocytosis?
- platelets >450 x 10^9/L
- MDS with del 5q
- MDS with inv(3) or t(3;3)
What percentage of MDS cases
have recurrent cytogenetic abnormalities ?
- 40-50%
IMP: acquired somatic mutations are seen in the vast majority of MDS cases at diagnosis
What is the general epidemiology
of MDS ?
- generally seen in older adults (median age: 70)
- MDS affecting children is rare and has it’s own diagnostic criteria
- male predominance
What are the microscopic findings
in MDS ?
- classification depends on:
- number of dysplastic lineages
- blasts in PB and BM
- and presence of RS
Note: the lineages with cytopenias are NOT necessarily the ones that contain dysplasia.
What has been observed regarding greater
% of blasts in the PB vs. BM ?
- in cases with more % blasts in PB (~13% of all MDS) compared to the BM
- those cases tend to act more aggressively
What is a general rule in making the diagnosis
of MDS ?
- cannot make the diagnosis without a detailed medication and drug history
- no case of MDS should be re-classified in a patient on growth factor therapy, including erythropoietin
What are things that can cause a clinical
and morphologic picture of MDS ?
- drugs
- infections
- autoimmune disorders
- metabolic deficiencies
What are the criteria for call a lineage dysplastic ?
- generally >10% of the precursor cells for erythroid and myeloid lineages
- >10% of megakaryocytes and must evaluate at least 30 megas
- some advocate for a threshold of 30-40% for dysplasia in megas
IMP: for cases with single lineage dysplasia, erythroids are usually the lineage that is dysplastic
What drug can cause ring sideroblast
formation ?
- Isoniazole
- it does this in the absence of vitamin B6 supplementation
Which medications can lead to
marked neutrophil hyposegmentation ?
- cotrimoxazole (antibiotic)
- immunosuppresants
- tacrolimus
- mycophenolate mofetil
- also can lead to erythroblastopenia
Which medical conditions can
clinically mimic MDS ?
- hypothyroidism
- infections
- autoimmune diseases
- PNH
- bone marrow lymphomatous involvement
- particularly LGL and Hairy cell leukemia
What is a feature on bone marrow biopsy
core of aggressive MDS ?
- Abnormal localization of immature precursors
- aggregates (3-5 cells) or clusters (>5 cells)
- they are usually localized in the center of the bone and away from bony trabeculae
What are some features that help differentiate
hypoplastic MDS from aplastic anemia ?
- dysplasia (most often in the megakaryocytes)
- increased blasts identified by CD34 stain
- abnormal karyotype
- most often trisomy 8
- although this can occasionally be seen in aplastic anemias
- most often trisomy 8
IMP: MDS-associated somatic mutations have been reported in as many as 1/3 of aplastic anemia patients
What must be excluded when considering
a diagnosis of hypoplastic MDS ?
- must exclude marrow injury due to a toxin, infection or autimmune disorder
What marrow finding, independent of the blast count,
indicates an aggressive clinical course in MDS?
- significant degrees of myelofibrosis (grade 2-3)
- seen in ~10-15% of MDS cases
- not a significant subtype but these patients tend to do worse
- blast counts may not be accurate due to significant fibrosis and hemodilute aspirates
- unlike PMF, MDS with fibrosis is NOT associated with splenomegaly, leukoerythroblastosis or intrasinusoidal hematopoiesis
What are the immunophenotypic changes in
the myeloids in MDS ?
- abnormal or asynchronous maturation patterns
- asynchrony of CD15 and CD16 in granulocytes
- altered expression of CD13 in relation to CD11b or CD16
- aberrant expression of CD7 or CD56 on:
- progenitors
- granulocytes
- monocytes
Note: also will have decreased hematogones in MDS
What are the immunophenotypic findings
of erythroids in MDS ?
- increased coefficient of variation
- decreased intensity of CD71 or CD36 expression
What is loss of 17p associated with ?
- MDS or AML with pseudo-Pelger Huet anomaly
- vacuolated, small neutrophils
- TP53 mutation
- unfavorable clinical course
- most common in therapy related MDS
What is usually seen in a complex
karyotype and what is the prognosis ?
- by definition >3 abnormalities
- usually have abnormalities in:
- chromosome 5 and or 7
- del 5q or t5q or loss of chromosome 7 or del 7q
- chromosome 5 and or 7
- generally associated with a poor clinical course
What are the morphologic
correlates for del 20q ?
- dysmegakaryopoiesis
- thrombocytopenia
What are the morphologic
correlates in inv(3) or t(3;3) ?
- abnormal megakaryocytes
- thrombocytosis
What clonal cytogenetic abnormalities
when present alone do NOT suffice for
a diagnosis of MDS ?
- loss of Y chromosome
- gain of chromosome 8
- del 20q
Note:
- these can be seen in other conditions. If no morphologic defining critieria then these do not count.
What unbalanced chromosomal abnormalities in the setting
of unexplained cytopenias but no
definitive dysplasia are enough to call MDS-U ?
- loss of chromosome 7 or del 7q
- del 5q or t5q
- isochromsomes 17q or t(17p)
- loss of chromsomes 13 or del 13q
- del 11q
- del 12p or t(12p)
- del 9q
- idic(x)(q13)
What balanced chromosomal aberrations in the setting of cytopenias
but no morphologic dysplasia
are enough to diagnose MDS-U ?
- t(11;16)
- t(3;21)
- t(1;3)
- t(2;11)
- inv(3) or t(3;3)
- t(6;9)
Note: cytogenetic abnormalities are present in ~50% of MDS cases. 80-90% of cases have somatic mutations in recurring genes.
Which mutations when present are
associated with severe granulocytic dysplasia ?
- ASXL1
- RUNX1
- TP53
- SRSF2
Why are somatic mutations alone
NOT enough to diagnose MDS ?
- these mutations can occur in healthy individuals without evidence of MDS
- even in the setting of cytopenia
Which is the only somatic mutation
that has it’s own MDS diagnostic category ?
- SF3B1
- only one infuencing MDS subtype
What are the low-risk MDS
groups ?
- MDS with single lineage dysplasia
- MDS with ring sideroblasts and single lineage dysplasia
- MDS with isolated del 5q
What is the intermediate risk group
for MDS ?
- MDS with multi-lineage dysplasia
- MDS with ring sideroblasts and multi-lineage dysplasia
What is the high risk MDS group?
- MDS with excess blasts
What two mutations tend to affect
MDS response to hypomethylating agents?
- TET2
- DNMT3A
How does TP53 mutation affect treatment
in MDS del 5q ?
- MDS del 5q is usually sensitive to Lenalidomide
- with TP53 mutation it becomes insensitive
Note: TP53 is a poor prognostic indicator and shows more aggressive disease
Which mutations when present show conflicting
data or a neutral impact on prognosis in MDS ?
- TET2 (DNA methylation)
- ZRSR2 (RNA splicing)
- IDH1/IDH2 (DNA methylation)
What gene confers a good prognosis
in MDS?
- SF3B1 (RNA splicing)
What are the transcription factors
genes that confer an adverse prognosis in MDS ?
- BCOR
- NRAS
- RUNX1
What are the RNA splicing genes that
confer an adverse prognosis in MDS?
- SRSF2
- U2AF1
What are the histone modifying genes that
confer an adverse prognosis in MDS ?
- ASXL1
- EZH2
What are the other gene categories/genes
that confer an adverse prognosis in MDS ?
- DNMT3A (DNA methylator)
- TP53 (tumor suppressor)
- STAG2 (cohesin complex)
- CBL (signalling)
What defining cytogenetic abnormalities
are considered to have very good prognosis ?
- loss of Y chromosom
- del 11q
What defining cytogenetic abnormalities
have a good prognosis ?
- Normal karyotype
- del 5q
- del 12p
- del 20q
- double, including del 5q
What defining cytogenetic abnormalities have
an intermediate prognosis in MDS ?
- del 7q
- gain of chromosome 8
- gain of chromosom 9
- isochromosome 17q
- single or double abnormalities not specified in other groups
- two or more independent non-complex clones
What defining cytogenetic abnormlities are
considered a poor prognostic factor ?
- loss of chromosome 7
- inv(3), t(3q), or del(3q)
- double including loss of chromosome 7 or del 7q
- complex karyotype
What is generally a very poor
prognostic group cytogenetically ?
- > 3 abnormalities
- complex karyotype
