Myelodysplastic Syndrom and Myeloproliferative Neoplasms

Question 1

Myelodysplastic syndrome

Answer 1

MDS is a group of conditions where the marrow is replaced by a malignant clone, derived from a transformed stem cell or progenitor cell. Theses cells were on the path for myeloid cells.

Question 2

MDS is characterized by

Answer 2

1) ineffective hematopoiesis: the clone is NOT able to make normal functioning blood cells. In fact, they are often die before leaving the marrow, and usually look abnormal (dysplastic)
2) increased risk of transformation to acute leukemia: MDS is often regarded as a precursor to acute myeloid leukemia (AML)

Question 3

Primary idiopathic MDS

Answer 3

Median age of diagnosis: 70, usually over 50. Incidence is 3-5 cases per 100K persons per year.

Question 4

Secondary MDS (usually therapy related MDS)

Answer 4

1) occurs as a part of the spectrum of therapy-related AML. 2) Usually diagnosed 2-8 years following therapy with DNA-alkylating agents or ionizing radiation. 3) Usually contains complex karyotype with whole or partial deletions of chromosomes 5 and/or 7

Question 5

MDA Diagnosis

Answer 5

1) considered in setting of persistent (at least several months) peripheral cytopenia in one or more lineages that canno be otherwise explained.
2) isolated persistent neutropenia and isolated persistent throbocytopenia are usually NOT due to MDS.
3) persistent cytopenia in 2 or more lineages in a patient of advanced age is suspicious for MDS.

Question 6

Diagnosis can be established with (in the setting of persistent cytopenia)…

Answer 6

1) morphologic evidence of dysplasia. 2) increased myeloblasts, but less than 20% of blood and marrow cells. 3) presence of clonal cytogenetic abnormality.

Question 7

Morphologic evidence of dysplasia

Answer 7

when more than 10% of the cells in one lienage appear DYSPLASTIC that qualifies as dyshematopoiesis. Can be subclassified as dyserthropoiesis, dysgranulopoiesis, dysmegakarypoiesis.

Question 8

MORPHOLOGIC EVIDENCE OF DYSPLASIA:

DYSERYTHROPOIESIS

Answer 8

megaloblastoid chromatin patterns in RBC precursors, nuclear irregularities. prominent ring Sideroblasts

Question 9

MORPHOLOGIC EVIDENCE OF DYSPLASIA: Dysgranulopoiesis

Answer 9

poor cytoplasmic granulation (hypogranular). Ex) neutrophils - 2 nuclear lobes called pelgeroid

Question 10

MORPHOLOGIC EVIDENCE OF DYSPLASIA:

dysmegakaryopoiesis

Answer 10

small often hypolobated or non-lobated nuclei

Question 11

Cytogenetic evidence of dysplasia

Answer 11

The presence of a clonal cytogenetic abnormality in the marrow of a persons with persistent cytopenia is strong evidence for MDS. Ex) complex karyotype with whole or partial deletions of chromosomes 5 and/or 7, isolated deletion 5q, trisomy 8

Question 12

Potential pitfall secondary myelodysplasia

Answer 12

Pt with suspected MDS, but neg for elevated myeloblasts and neg for clonal cytogenetic abnormality, BUT have morphological dysplasia, be sure the EXCLUDE POTENTIAL causes of secondary MDS including: vitamin deficiency, toxin exposure, exposure to cetrain drugs, viral infections.

Question 13

Low grade MDS

Answer 13

myeloblasts are not increased in frequency (myeloblasts account for <2% of blood cells)

Question 14

High grade MDS

Answer 14

myeloblasts are increased in frequency, but less than 20% (myeloblasts account for 5-19% of marrow cells, and/or 3-19% of blood cells)

Question 15

Types of low grade MDS

Answer 15

1) refractory cytopenia with unilineage dysplasia. (only 2% of cases transform to AML)
2) Refractory cytopenia with multilineage dysplasia (10% of cases transform to AML by 2 years).

Question 16

Types of high grade MDS

Answer 16

1) Refractory anemia with Excess blasts-1. (median survival of 16 months - 25% will transform to AML)
2) Refractory anemia with excess blasts-2 (median survival of 9 months, - 33% will turn to AML)

Question 17

Myeloproliferative Neoplasms

Answer 17

1) Clonal hematopoietic neoplasm arising from a transformed hematopoietic stem cell
2) The neoplastic clone usually partially or entirely replaces the normal marrow cells in multiple lineages
3) The neoplastic clone usually gives rise to increased numbers of normal (not dysplastic) blood cells in one or more lineages
4) Usually occurs in middle-aged to elderly adults, rare in children
5) Incidence of 6-10 cases per 100K persons per year

Question 18

Common themes in MPNs (myeloproliferative neoplasms)

Answer 18

1) early disease characterized by increase in one or more blood cell types, with corresponding increase in marrow cellularity
2) patients often have splenomegaly and or hepatomegaly.
3) usually have insidious onset
4) END STAGE: without treatment progress to excessive marrow firbosis with bone marrow failure (can relate to splenomegaly). Also can have transformation to acute leukemia.

Question 19

Myeloproliferative neoplasm classifications

Answer 19

historically by types of cells being overproduced and appearnce of marrow on biopsy. WHO scheme is adding cytogenic and molecular findings.

Question 20

MPNs types

Answer 20

Chronic myelogenous leukemia (CML- most common), Polycythemia Vera (PV - “a lot of blood cells, really”), primary myelofibrosis (PMF), Essential thromocythemia (ET)

Question 21

CHRONIC MYELOGENOUS LEUKEMIA (CML)

Answer 21

CML is an MPN that manifests primarily as a persistent neutrophilic leukocytosis, and is associated with the presence of a BCR-ABL1 gene fusion

Question 22

CML clinical findings

Answer 22

1) non specific signs/symptoms - night sweats, weight loss, splenomegaly, anemia.
2) significant minority of Pts are asymptomatic at diagnosis.
3) 1-2 cases per 100K persons per year
4) typical age at diagnosis 40-60. Rare in children and young adults.

Question 23

CML-chronic phase

Answer 23

Usually stable and characterized by: prominent leukocytosis due to prominent neutrophilia. Increased basophils in blood. Often increased platelets in blood. Markedly hypercellular bone marrow w/ prominent granulocytic hyperplasia.

Question 24

CML - Blast phase

Answer 24

Blast phase defined by 20% or more blasts in the marrow or blood. In the cases of blast-phase 70% the blasts are myeloblasts, 30% are lymphoblasts. CML may proceed directly from chronic phase to blast phase.

Question 25

CML genetics

Answer 25

defined by presence of BCR-ABL1 gene fusion.. der(22)t(9:22). Called the philadelphia chromosome. Note here the fusion protein break point is 210KD, the ALL is 190 KD

Question 26

CML Diagnosis

Answer 26

documenting typical findings in blood and marrow. Documenting the presence of BCR-ABL1 fusion gene.

Question 27

CML treatment/prognosis

Answer 27

untreated CML has median survival or 2-3 years. Former non-targeted treatments extended median survival by a few years.
Protein Tyrosne kinase inhibitors have improved pronosis for CML– 5 year progression free survival and 5 year overall survival rates around 80-85%
First was Gleevec (imatinib). Now there are a lot of tyrosine kinase inhibitors.

Question 28

Polycythemia Vera (PV)

Answer 28

NEGATIVE FOR BCR/ABL.
a MPN chielfy characterized by an increase in RBC mass.
Usually also see increase in neutrophils and platelets. Bone marrow biopsy shows clusters of bizarre megakarycotes.
ESSENTIALLY ALL CASES OF PV CONTAINS activating mutation of JAK2, usually V617F point mutation

Question 29

PV pitfall

Answer 29

persistent erythrocytosis, but no JAK2 mutation consider secondary erythrocytosis seen in: smokers, chornic hypoxia, certain hemoglobin disorders.

Question 30

Presenting symptoms of PV patients

Answer 30

headaches, plethora (dusky reddish skin), pruritus (itching), paresthesias (pins and needles) splenomegaly, hepatomegaly.

Question 31

PV diagnosed in polycythemic phase

Answer 31

with increased blood cell counts. Then can progress to SPENT PHASE with extensive marrow fibrosis and fall in blood cell counts

Question 32

Complications of PV

Answer 32

venous or arterial thrombosis. Thrombosis of mesenteric vein, portal vein, or splenic vein should always raise posibility of PV

Question 33

PV prognosis

Answer 33

good with median survival times of 10-20 years.

Question 34

therapeutic methods

Answer 34

are serial phlebotomy, aspirin therapy. Chemotherapy could transform into acute leukemia

Question 35

Primary myelofirbosis (PMF)

Answer 35

characterized by granulocytic and megakaryocytic hyperplasia, but no erythrocytosis.
JAK2 mutations are present in 50% of PMF cases.

Question 36

PMF starts in prefibrotic stage

Answer 36

characterized by hypercellular marrow with granulocytic and megakaryocytic hyperplasia.

Question 37

PMF eventually profresses to fibrotic stage

Answer 37

characterized by significant reticulin fibrosis of the marrow. Leukoerythroblastosis of blood. Falling blood cell counts. Enlargement of organs due to extramedullary hematopoiesis.

Question 38

Primary myelofibrosis prognosis

Answer 38

if diagnoses in fibrotic stage, PMF has median survival of 5 years. Most deaths in PMF are due to bone marrow failure. A minority of PMF cases may transform to AML.

Question 39

Essential thrombocythemia (ET)

Answer 39

ET is an MPN characterized by a persistent thrombocytosis. It lacks the marrow granulocytic hyperplasia often seen in PMF, and the atypical megakaryocytes in ET are even larger than those in PMF

• JAK2 mutations are present in around 50% of ET cases
• Cases lacking JAK2 mutations often have mutations of MPL or CALR

Question 40

Diagnosis of ET

Answer 40

50% based on CBC results while asymptomatic.

Question 41

Signs and symptoms of ET include

Answer 41

transiet ischemia attahcs, digital ischemia, arterial or venous thrombosis. NO spenomegaly.

Question 42

Prognosis of ET

Answer 42

ET is indolent disease, with median survival of over 10 years. Only rarely does ET transform to AML or progress to myelofibrosis

Question 43

Chronic phase CML histology

Answer 43

• Markedly Hypercellular Marrow with Granulocytic Hyperplasia
• Frequent Small Megakaryocytes with Non-Lobated Nuclei
• Peripheral Blood with Increased Neutrophilic Granulocytes

Question 44

Polycythemia Vera histology

Answer 44

Marrow with Trilineage Hyperplasia and Bizarre Megakaryocytes