Topic 19-23,31: myeloid neoplasia

Question 1

myeloproliferative disorders all have certain characteristics in common

Answer 1

• 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

Question 2

CML is what type of cell proliferation? mutation?

Answer 2

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

Question 3

In CML, the chronic phase can be followed by which 2nd phase?

Answer 3

50% of the time cml enters a blast crisis, 30% looks like B-ALL and 70% looks like AML

rarely it enters myelofibrosis

Question 4

CML is treated how

Answer 4

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

Question 5

Primary myelofibrosis is the proliferation of which cells? which mutations?

Answer 5

granulocytes and megakaryocytes

genetic mutation in JAK2 (valine to phenylalanine at amino acid residue 617)

Question 6

what are the two phases of PMF?

Answer 6

• 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)

Question 7

what is the peripheral blood smear of PMF?

Answer 7

RBC: poikilocytosis, teardrop cells
large platelets
nucleated erythroid precursors present

Question 8

PV (polycythemia vera) is the proliferation of which cells? which mutations?

Answer 8

erythroid, granulocyte and megakaryocytic. –> increased cell mass
genetic mutation in JAK2 (valine to phenylalanine at amino acid residue 617)

Question 9

difference bts PV and polycythemia?

Answer 9

in pv, there is low EPO because the tyrosine kinase acts independent of growth factors

Question 10

symptoms of pv

Answer 10

• spleen and liver enlargement
• thrombi and infarcts
• hemorrhage due to blood vessel distension and dysfunctional platelets
• hypercellular BM
• trousseau’s phenomenon

Question 11

what are the two phases of PV?

Answer 11

• proliferative phase

- spent phase (after 10 years or so) with bm fibrosis

Question 12

ET (essential thrombocythemia) is the proliferation of which cells? which mutations?

Answer 12

megakaryocytic. –> increased platelets

genetic mutation in JAK2 (valine to phenylalanine at amino acid residue 617)

Question 13

morphology of ET? treatment?

Answer 13

atypical huge megakaryocytes

plasmapheresis is the treatment, maybe low dose chemo

Question 14

splenomegaly can be divided up into 3 categories

what are some general consequences?

Answer 14

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)

Question 15

massive splenomegaly causes

Answer 15

• myeloproliferative and lymphoproliferative disorders
• lymphoma
• malaria
• gaucher disease

think “all hematological disorders makes grouchy mosquitos”

Question 16

moderate splenomegaly causes

Answer 16

• 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”

Question 17

mild splenomegaly

Answer 17

• acute splenitis (bacteremia)
• mono
• septicemia, lupus

think bacteria and viruses

Question 18

hypersplenium is what and caused by what?

Answer 18

when the spleen removes too many blood components

caused by widening of the splenic cords, infections and abnormal cell components

Question 19

what histological thing shows that spleen isn’t functioning anymore?

Answer 19

howell-jolly bodies

Question 20

disorders of the thymus?

Answer 20

• thymic hyperplasia

- thymoma

Question 21

thymic hyperplasia occurs in which patients?

Answer 21

myasthenia gravis mostly, sometimes SLE and RA

Question 22

thymoma is what?

Answer 22

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

Question 23

MDS (myelodysplastic syndrome) is what condition? causes? what is the mutation?

Answer 23

-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

Question 24

the 5q deletion in MDS is special how?

Answer 24

loss of miRNA and ribosomal coding –> severe anemia with inc platelet count and needs treatment with thalidomide analogs

Question 25

abnormal hematopoietic precursors in MDS

Answer 25

• megaloblastoid erthyroid precursors
• ringed sideroblasts - erythroid cells with iron deposits in mito
• abnormal granulocytes
• small megakaryocytes with single small nuclei

Question 26

MDS sometimes transforms to what? treatment and survival?

Answer 26

10-40% transforms to AML

poor response to chemo and survival is 9-29 months

Question 27

AML (acute myeloid leukemia) is classified by WHO into 4 categories

Answer 27

• AML associated with genetic mutations
• AML associated with dysplasia
• AML that occur after genotoxic chemotherapy
• AML that does not fit previous categories

Question 28

what is the mutation associated with AML? treatment

Answer 28

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.

Question 29

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?

Answer 29

• 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)