Done By :

Rasha Rakan & Shady Soghayr

Corrected by :

Sajedah Nizar

WHAT DOCTOR ADDED WILL BE BETWEEN 2 LINES IN SOME PARTS OF THE SHEETS, THE OTHER PARTS IS GOING TO BE IN RED BOLD FONT

Myelodysplastic syndrome (MDS) A multipotent stem cell that can differentiate into any of the myeloid

lineage cells (RBCs, granulocytes, megakaryocytes)

…become abnormal and proliferate (clonal proliferation), and this abnormal clone will have

-ineffective

& -disordered differentiation

Ineffective hematopoiesis & high risk of transformation to AML

• The marrow: usually is hypercellular or normocellular • The peripheral blood: one or more cytopenias • Most cases are idiopathic

…but some: after chemotherapy with alkylating agents or exposure to ionizing radiation therapy

The MDS and myeloproliferative neoplasms can transform to AML and some of them to acute lymphoblastic leukemia(ALL). but in general their prognosis is better than (AML) , because not all of their cells are ( –blasts) and they show their symptoms slower , but unfortunately they lead to death.

The multipotent stem cells have mutated genes, and that makes it abnormal and the cells it differentiates to are abnormal (ineffective hematopoiesis).

In peripheral blood we will see cytopenias (less RBC'S) in addition to leukopenia and thrombocytopenia (and this means that the patients will

come with infections (leukopenia) hemorrhages (thrombocytopenia) and anemia (cytopenia) .

MDS, common genetic/epigenetic abnormalities

• Epigenetic factors

… DNA methylation, histone modifications…etc. • RNA splicing factors

… Commonly associated with ring sideroblasts • Transcription factors • 10%...loss-off function mutations in the tumor suppressor gene

TP53

…poor outcome • Also: chromosomal abnormalities, including monosomies 5 and

7, deletions of 5q, 7q, and 20q, and trisomy 8 Epigenetic abnormalities are common. Abnormal RNA splicing proteins (abnormal RNA splicing abnormal proteins) . Ring sideroblasts is associated with RNA splicing abnormalities. Ring sideroblast : abnormal nucleated erythroblasts (precursors to mature red blood cells) with granules of iron accumulated in the mitochondria surrounding the nucleus. The abnormality in the TP53 is associated with poor prognosis.

MDS, morphology

• Abnormal erythroid precursors:

-megaloblastoid

or -ring sideroblasts • Abnormal granulocyte precursors:

-abnormal granules

or -abnormal nuclei • Abnormal megakaryocytes:

-small

or -single small nuclei

or -multiple separate nuclei (usually lobulated )

MDS, clinical notes

• Age: mostly 50-70 years • Symptoms and signs related to cytopenias

…anemia

…infections

…hemorrhages • 10-40%: transform to AML

We need to differentiate between the MDS and the megaloblastic

anemia caused by B12 or folic acid deficiency (we have to do anything

to exclude "MDS" when we see megaloblastoid in the peripheral blood.

Myeloproliferative neoplasms

…mutated, constitutively activated tyrosine kinases or other acquired aberrations in signaling pathways

…growth factor independence (extra : here we have tyrosine kinase is overactive . it's not affected by increase the binding of growth factor , but because of a mutation )

…tyrosine kinase inhibitors can be used

…neoplastic cells seed secondary lymphoid and hematopoietic organs and cause abnormal hematopoiesis…hepatosplenomegaly

• Four major diagnostic entities

-Chronic myeloid leukemia (CML)

-Polycythemia vera

-Primary myelofibrosis

-Essential thrombocythemia ( we aren't going to talk about it )

Myeloproliferative neoplasms are associated with tyrosine kinases or

with it's signaling pathways (this is important in the targeted therapy , i.e

: we control at the level of the mutated gene )

We use the tyrosine kinase inhibitors because the tyrosine will be

overactive in this case.

In the myeloproliferative neoplasms hepatosplenomegaly is common,

because of the extramedullary hematopoiesis.

Genetics

• CML…characteristic abnormality for CML, the BCR-ABL fusion gene

…constitutively active BCR-ABL tyrosine kinase • Activating mutations in the tyrosine kinase JAK2

…in virtually all cases of polycythemia vera and about 50% of cases of primary myelofibrosis and essential thrombocythemia

• Others

Myeloproliferative neoplasms, cont’d • All myeloproliferative neoplasms have variable propensities to

transform to:

-a “spent phase” resembling primary myelofibrosis

or

-“blast crisis” identical to acute leukemia,

…both presumably triggered by the acquisition of other somatic mutations

A translocation between chromosomes 9 & 22,and a gene fusion of BCR-ABL (Philadelphia chromosome) , so when ABL move to BCR ,this causes an increase in the production of ABL(oncogene)

ABL: tyrosine kinase

JAK2 is associated with polysythemia vera and may come with myelofibrosis and essential polysythemia

Blast crises: if a myeloproliferative disorder transformed to acute leukemia by additional mutation .

The spent phase can have cytopenias and splenomegaly

Spent phase leads to Fibrosis in bone marrow extramedullary hematopoiesis splenomegaly

CML

• Peak incidence: fourth and fifth decades • Distinguished from other myeloproliferative neoplasms by:

chimeric BCR-ABL gene: derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9

• In about 95% of cases, the BCR-ABL gene is the product of a balanced (9;22)

Translocation that moves ABL from chromosome 9 to a position on chromosome 22 adjacent to BCR

…Although the Ph chromosome is highly characteristic of CML, it also is present in 25% of adult B cell–ALLs and a small subset of AMLs

• BCR-ABL does not inhibit differentiation, so:

…the early disease course is marked by excessive production of relatively normal blood cells, particularly granulocytes and platelets

• Leukocyte count is elevated, often exceeding 100,000 cells/μL • Circulating cells are predominantly neutrophils,

metamyelocytes, and myelocytes…among others (especially basophils)

• The bone marrow is hypercellular • Extensive extramedullary hematopoiesis...may affect spleen

blood supply…splenic infarcts

The BCR-ABL increases the proliferation but doesn't affect the

differentiation

CML can be distinguished from AML by the good differentiation (not

blasts), but increased number of cells

Sometimes the extramedullary hematopoiesis is very bad that it affects

the blood supply of the spleen, so it will cause splenic infarct.

CML can be detected by : (karyotype, fluorescence in situ hybridization FISH" ,

BCR) "

• Onset of CML is insidious slow

• The initial symptoms usually are nonspecific…easy fatigability,

weakness, weight loss

• Sometimes the first symptom is abdominal discomfort caused by splenomegaly

• Distinguish CML from a leukemoid reaction (a dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, and certain neoplasms it is like leukemia but it isn’t leukemia testing for the presence of the BCR-ABL fusion gene is important here .(large numbers of cells don’t necessary mean leukemia, we cannot decide if it's CML until we see BCR-ABL fusion gene. )

• Even without treatment, the median survival is 3 years Fatal, but still more indolent than acute leukemia It enters blast crisis either directly or enters accelerated phase then blast crisis:

• Half of CML cases enter an accelerated phase marked by:

…increasing anemia adding on the previous affected RBCs production and new thrombocytopenia instead of the thrombocytosis that happens in CML and this is an evidence that it is entering blast

crisis, will transform into a picture resembling acute leukemia (blast crisis)

• In other cases, blast crisis occurs abruptly, without an accelerated

phase

• Less commonly, CML progresses to spent phase a phase of extensive bone marrow fibrosis resembling primary myelofibrosis

• Tyrosine kinase inhibitors are effective…may become resistant Treatment drug of CML: Gleevec (brand name) = imatinib methylate (scientific name), this drug is very effective ,but has a high cost .

Polycythemia vera (PV)

• Strongly associated with activating point mutations in the tyrosine kinase JAK2

…acts in the signaling pathways downstream of the erythropoietin receptor which is the hormone responsible for proliferation of erythroid precursors to increase RBCs

and other growth factor receptors

• Excessive proliferation of erythroid **,granulocytic, and

megakaryocytic elements (panmyelosis) basophilia is important evidence, because it’s rare in normal people, but happens here and in CML .

** Hb is high in them (18) even though they aren’t smokers and RBCs number is so high in contrast of anemia Not only RBCs but all the Myeloid lineage can increase.

but most clinical signs and symptoms are related to an absolute increase in red cell mass the RBCs number increased, and can be neoplastic as in Polycythemia vera which results from mutation in a gene led to increased proliferation, and can be reactive results from hypoxia and thus increased erythropoietin secretion as smoking .

Viscosity of the blood related to increase red cell mass is one of the major problems/symptoms thrombosis PV Must be distinguished from relative polycythemia, which results from hemoconcentration High Hb but the reason is dehydration, water decreased but RBCs number didn’t change, only RBC's/ water concentration has changed .

(Polycythemia)- alone-, means increase in RBCs and it isn’t malignant proliferation, but this is not the same when we add the word “vera” It’s either absolute or relative.

• Low levels of serum erythropoietin, which is a reflection of the growth factor independent growth of the neoplastic clone receptors work abnormally, and proliferation happens without the need of erythropoietin, a lot of RBCs will inhibit its secretion, unlike reactive conditions and this is how we distinguish between them

• Increases in blood volume and viscosity everywhere

• The liver is enlarged due to congestion because of viscosity and often contains small foci of extramedullary hematopoiesis

• The spleen usually is slightly enlarged (250 to 300 g) because of

vascular congestion

• Risks: Thromboses and infarctions are common, particularly in

the heart, spleen, and kidneys

Platelets produced from the neoplastic clone often are dysfunctional, a derangement that contributes to the elevated risk of thrombosis and bleeding Problems of platelets, that are abnormal either excessive bleeding or excessive thrombosis

•

• As in CML, the peripheral blood often shows basophilia

• The bone marrow is hypercellular owing to increased numbers of

erythroid, myeloid, and megakaryocytic forms • Appears insidiously, usually in late middle age

• Plethoric محمر and often somewhat cyanotic مزرق facies in

the face

• Histamine released from the neoplastic basophils -pruritus because of basophils

-increased incidence of peptic ulceration because histamine increases HCL

• Thrombotic and hemorrhagic tendencies

• Hypertension

• Headache, dizziness, gastrointestinal symptoms, hematemesis and melena dark blackish stool because it contains ,استفراغ دمblood are common.

• Typical presentation for this disease is " a 40-50 years old

person has developed pruritus and plethoric after ahot shower – remember : after hot shower - ……. .

• Because of the high rate of cell turnover a lot of mitosis and apoptosis, and thus symptomatic gout (accumulation of uric acid in joints/hyperuricemia) is seen in 5% to 10% of cases

• Hematocrit is often 60% or greater

• The granulocyte count can be as high as 50,000 cells/μL

• The platelet count is often more than 400,000/μL normal count is 150,000-300,000/ μL

• Basophilia is common

• Platelets are functionally abnormal in most cases, and giant platelets and megakaryocyte fragments are often seen in the blood abnormal shape

• 30% of patients develop thrombotic complications, usually affecting the brain or heart

• Hepatic vein thrombosis giving rise to Budd-Chiari syndrome is an uncommon but grave complication

• Epistaxis and bleeding from gums

• In those receiving no treatment, death occurs from vascular complications within months

…however, the median survival is increased to about 10 years by lowering the red cell count to near normal through repeated phlebotomy تبرع بالدم / without treatment ,they only live for months . there’re risk for them to turn into AML

• Unfortunately, prolonged survival has shown a propensity for

polycythemia vera to evolve to a “spent phase”

…After an average interval of 10 years, 15% to 20% of cases undergo such a transformation ( AML or primary myelofibrosis )

• Inhibitors that target JAK2 have been approved for treatment

• Transformation to a “blast crisis” identical to AML also occurs,

but much less frequently than in CML

• Primary myelofibrosis The hallmark of primary myelofibrosis is:

obliterative marrow fibrosis, which reduces bone marrow

hematopoiesis and leads to:

…cytopenias ( anemia ) and extensive extramedullary hematopoiesis ( mainly splenomegaly)

• JAK-STAT signaling seems to be the underlying driver in almost all cases

• Transformation to AML occurs in 5% to 20% of cases • JAK2 inhibitors are effective.

• In peripheral blood smear:

Abnormal red cells that often exhibit bizarre shapes (poikilocytes, teardrop cells), and nucleated erythroid precursors are commonly seen along + immature white cells (myelocytes and metamyelocytes) = both together are called leukoerythroblastosis

• Abnormally large platelets often are present as well

clinical notes

• Usually older than 60 years • Progressive anemia + splenomegaly • Also abnormal platelets and risk of bleeding & thrombosis • 4-5 years but more difficult to treat than CML and PV • JAK2 inhibitors decrease the symptoms.

Please contact us if you have any note

GOOD LUCK ^^