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14 Cards in this Set

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Define myelodysplastic syndromes (MDS).
Group of acquired clonal hematopoietic stem cell d/o's characterized clinically and morphologically by ineffective hematopoiesis

Typical findings:
-- hypercellular dsypoietic marrow
-- intramedullary cell death
-- peripheral cytopenias
-- tendency to progress to acute myeloid leukemia (AML)

These disorders are neoplastic
What is dyspoiesis?
abnormal maturation (dysplastic) of the hematopoietic precursors in BM that can be detected morphologically and fxnally

In MDS:
-- all three cell lines of the marrow are involved
-- severity of each line involved is variable and the basis of classification
Pathophys of MDS?
Neoplastic transformation that most likely occurs at level of the earliest myeloid progenitor cell (committed progenitor cell)
-- RBCs
-- megakaryocytes
-- granulocytes
-- monocytes

Perhaps rarely at the primitive stem cell (involving myeloid AND lymphoid cells)

Clonal origin proven by cytogenetic studies and X-inactivation studies

Oncogenesis is a multistep process most likely involving activation of protooncogenes, inactivation of tumor suppressor genes, and mutations of antiapoptotic genes and cell cycle regulator genes.

RESULT:
-- impaired maturation of hematopoietic cells in marrow
-- increased rate of apoptosis
(above contributed to by overproduction of growth inhibitory cytokines)
Etiology of MDS?
Majority are idiopathic.

Some assoc w/ know previous exposure to chemo and/or radiation --> "secondary MDS" or "therapy-related MDS"

Therapy related often assoc w:
-- alkylator agents (chlorambucil, malphalan, etc)
-- most cases (>90%) will have partial deletions or total loss of chrom 5 and/or 7, and other complex cytogenetic aberrations

May be seen in pts w/ rare inherited chrom instability syndromes:
-- Fanconi's anemia
-- ataxia telangectasia
Epidemiology of MDS?
More common than acute leukemia, w/ a current incidence of 10/100K per year; incidence is increasing

Elderly pop affected, 65-70yrs being peak incidence.
MDS seen in young adults and pediatric pts
MDS symptoms?
~50% are asymptomatic at time of Dx --> MDS suspected due to abnormal CBC findings

Other symptoms related to:

Anemia
-- fatigue
-- dyspnea
-- exertion angina

Leukopenia
-- recurrent infections

Thrombocytopenia
-- ecchymoses
-- petechia

Hepatosplenomegaly and adenopathy are RARE
MDS diagnosis?
Initally suspected by clinical findings and CBC.

Confirmed by peripheral blood smear, BM smear, and biopsy.

Morphologic features of dyspoiesis assessed for each of the major cell lines

Peripheral blood -- cytopenias

BM -- hypercellular
Dyserythropoiesis
PERIPHERAL BLOOD:
-- anemia, often macrocytic
-- variable anisocytosis and poikiolocytosis
-- frequently macroovalocytes
-- prominent basophilic stippling sometimes present

BONE MARROW:
-- erythroid precursors --> varying degrees of megaloblastoid maturation
-- nuclear-cytoplasmic dyssynchrony
-- multinucleation
-- nuclear fragmentation
-- possibly ringed sideroblasts
Dysmyelopoiesis
PERIPHERAL BLOOD:
-- leukopenia w/ possibly hypolobated, hypogranular PMNs (pseudo-Pelger-Huet)
-- can be PMN dysfxn w/ increased infections
-- Precursor cells including blasts may be in circ
-- may be abnormal and immature monocytes

BONE MARROW:
-- come abnormal morphology w/ hypogranulation of the precursors (like seen in periphery)
-- number of myeloblasts present are impt for classif and prognosis
Dysmegakaryopoiesis
PERIPHERAL BLOOD:
-- thrombocytopenia
-- possibly large, hypogranular platelets w/ decreased fxn

BONE MARROW:
-- frequently decreased numbers megakaryocytes w/ abnormal morphology
-- separate, individual nuclei (instead of single, multilobated nucleus) OR
-- single non-lobated nuclei AND/OR
-- micro-megakaryocytes
MDS bone marrow biopsy?
Hypercellular in most cases
-- 15% are hypocellular

Few cases have diffuse marrow fibrosis, simulating MPD of myelofibrosis w/ myeloid metaplasia (MMM)
MDS cytogenetic studies?
Approx 75% of cases will have clonal, acquired chrom aberrations
-- partial chrom deletions
-- complete loss

Poor prognosis assoc with:
-- -7
-- presence of complex (>2 aberrations) findings

Good risk findings include:
-- normal karyotype
-- isolated del(5q)
-- isolated del(20q)

All other cytogenetic findings assoc w/ intermed risk
Prognosis of MDS?
Most related to
1. severity of peripheral blood
2. marrow findings at time of dx
3. cytogenetics

Better prognostic types are RA and RARS (5-6yrs)

Worse prognostic type is RAEB-1 (1-3yrs)
MDS cure?
None

Approx 30% progress to AML

Remainder succumb to complications of BM failure
-- hemorrhage
-- infection

Trtment:
-- supportive care
-- transfusions
-- antibiotics
-- growth factors may result in temporary improvement, but does not prolong overall survival

Chemo given only once transformation to AML has occurred
-- low remission rate
-- remission (if occurs) is of short duration

BM transplant is the only possible hope for long-term remission and possible cure