Topic 19-23,31: myeloid neoplasia Flashcards
myeloproliferative disorders all have certain characteristics in common
- Biphasic
1st: proliferative phase
2nd: may transform to acute leukemia (“blast crisis”), in which there is accumulation of immature cells, or to myelofibrosis, in which the megakaryocytes make fibrosis → destruction of the bone marrow and hemopoiesis. - all are tyrosine kinase disorders - either the t(9,22) BCR/ABL fusion or JAK2/V617F
- 5-10 year survival rate
CML is what type of cell proliferation? mutation?
only in granulocytes and caused by a BCR-ABL gene fusion. t(9,22) where ABL is moved to BCR’s location on chrom 22.
BCR-ABL is the philadelphia chromosome that causes uncontrolled division because it is an abnormal tyrosine kinase
In CML, the chronic phase can be followed by which 2nd phase?
50% of the time cml enters a blast crisis, 30% looks like B-ALL and 70% looks like AML
rarely it enters myelofibrosis
CML is treated how
Imatinib (brand name gleevec) binds to the active tyrosine kinase and inactivate it. the gene is still there but the effect is gone,however resistance is common and the drug is expensive
Primary myelofibrosis is the proliferation of which cells? which mutations?
granulocytes and megakaryocytes
genetic mutation in JAK2 (valine to phenylalanine at amino acid residue 617)
what are the two phases of PMF?
- cellular phase there is no myelofibrosis, and the peripheral blood WBC and platelet counts are elevated
- Fibrotic phase: neoplastic megakaryocytes release PDGF and TGFβ → stimulation of marrow fibroblasts to deposit collagen → fibrosis in the bone marrow → pancytopenia and extramedullary hematopoiesis → splenomegaly (+moderate hepatomegaly)
what is the peripheral blood smear of PMF?
RBC: poikilocytosis, teardrop cells
large platelets
nucleated erythroid precursors present
PV (polycythemia vera) is the proliferation of which cells? which mutations?
erythroid, granulocyte and megakaryocytic. –> increased cell mass
genetic mutation in JAK2 (valine to phenylalanine at amino acid residue 617)
difference bts PV and polycythemia?
in pv, there is low EPO because the tyrosine kinase acts independent of growth factors
symptoms of pv
- spleen and liver enlargement
- thrombi and infarcts
- hemorrhage due to blood vessel distension and dysfunctional platelets
- hypercellular BM
- trousseau’s phenomenon
what are the two phases of PV?
- proliferative phase
- spent phase (after 10 years or so) with bm fibrosis
ET (essential thrombocythemia) is the proliferation of which cells? which mutations?
megakaryocytic. –> increased platelets
genetic mutation in JAK2 (valine to phenylalanine at amino acid residue 617)
morphology of ET? treatment?
atypical huge megakaryocytes
plasmapheresis is the treatment, maybe low dose chemo
splenomegaly can be divided up into 3 categories
what are some general consequences?
massive splenomegaly >1000 g
moderate 500-1000 g
mild <500 g
remove excess numbers of blood cells, splenic rupture and thrombocytopenia (red pulp sequesters platelets)
massive splenomegaly causes
- myeloproliferative and lymphoproliferative disorders
- lymphoma
- malaria
- gaucher disease
think “all hematological disorders makes grouchy mosquitos”
moderate splenomegaly causes
- chronic congestive splenomegaly due to portal HT
- acute leukemia
- spherocytosis and thalassemia
- autoimmune hemolytic anemia
- amyloidosis
- tb
think “too much blood or not enough RBCs”
mild splenomegaly
- acute splenitis (bacteremia)
- mono
- septicemia, lupus
think bacteria and viruses
hypersplenium is what and caused by what?
when the spleen removes too many blood components
caused by widening of the splenic cords, infections and abnormal cell components
what histological thing shows that spleen isn’t functioning anymore?
howell-jolly bodies
disorders of the thymus?
- thymic hyperplasia
- thymoma
thymic hyperplasia occurs in which patients?
myasthenia gravis mostly, sometimes SLE and RA
thymoma is what?
tumor of thymic epithelial cells
type I: locally invasive, 25% of thymomas, occasionally metastasize
type II: 5%, invasive and metastasize to lungs, looks like squamous cell carcinoma
MDS (myelodysplastic syndrome) is what condition? causes? what is the mutation?
-Bm is partially/fully replaced by clonal progeny of transformed multipotent stem cells that differentiate in a disorganized fashion, leading to cytopenias
can occur due to mutations (idiopathic) or after radiation therapy/chemo
-clonal abnormalities in 70%, usually deletions of whole/parts of chromosome:
monosomy 5 or 7
trisomy 8
deletion of 5q, 7q, or 20q
the 5q deletion in MDS is special how?
loss of miRNA and ribosomal coding –> severe anemia with inc platelet count and needs treatment with thalidomide analogs
abnormal hematopoietic precursors in MDS
- megaloblastoid erthyroid precursors
- ringed sideroblasts - erythroid cells with iron deposits in mito
- abnormal granulocytes
- small megakaryocytes with single small nuclei
MDS sometimes transforms to what? treatment and survival?
10-40% transforms to AML
poor response to chemo and survival is 9-29 months
AML (acute myeloid leukemia) is classified by WHO into 4 categories
- AML associated with genetic mutations
- AML associated with dysplasia
- AML that occur after genotoxic chemotherapy
- AML that does not fit previous categories
what is the mutation associated with AML? treatment
t(15,17) fusion of PML to the retinoic acid receptor a (RARA) gene which then blocks myeloid differentiation at the promyelocytic stage
treat with vit A analog (ATRA) + arsenic trioxide (induce degradation of gene)
Other mutations:
- t(8;21) CBFα/ETO. good prognostic marker
- Inv (16) CBFβ/MYH11. good prognostic marker
- t(11q invariable) MLL mutation. low prognostic marker.
what histological things can you see in AML? what marker is used to distinguish AML and ALL?
tumor cells are associated with a combo of which myeloid associated antigens?
- auer rods
- MPO with immunohistochem
- CD33 for differentiation
- CD 13, 14, 15, 64 and 117 (think 13, 14, 15, (1)6 (and 6+4 =10) and (1)17)
