Myeloproliferative Neoplasms Flashcards by LEDESMA, Anne Gelika

clonal hematopoietic stem cell disorders that result in excessive production and overaccumulation of erythrocytes, granulocytes, and platelets in some combination in bone marrow, peripheral blood, and body tissues

MYELOPROLIFERATIVE NEOPLASMS (MPN)

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“myelo” is associated with:

bone marrow and hematopoietic cells
myeloid cells series (RBC, granulocytes, plt.)

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In MPN, these cells have an excessive production and overaccumulation

erythrocytes
granulocytes
platelets

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4 major conditions associated with MPNs

Chronic myeloid leukemia (CML)
Polycythemia vera (PV)
Essential thrombocytopenia (ET)
Primary myelofibrosis (PMF)

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MPNs with JAK2 mutation

Polycythemia vera (PV)
Essential thrombocytopenia (ET)
Primary myelofibrosis (PMF)

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Chronic
* Predominant cell type – ?
* Onset: ?
* WBC count – ?
* Production – ?

Predominant cell type – mature
Onset: insidious/gradual (with harmful effects)
WBC count – increased
Production – lower (months to years)

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Myelogenous means?

arise from myeloid series cells

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Consistently associated with BCR-ABL fusion gene located in Philadelphia chromosome

CHRONIC MYELOGENOUS LEUKEMIA

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aka Philadelphia chromosome

changed chromosome 22

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gene and the gene location associated with CML

BCR-ABL fusion gene
located in Philadelphia chromosome

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reciprocal translocation of DNA between chromosomes 9 and 22

Philadelphia chromosome (changed chromosome 22)

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Condition with overproduction of tyrosine kinase

CHRONIC MYELOGENOUS LEUKEMIA

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promotes AML cells survival and proliferation

tyrosine kinase

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Condition with large numbers of myeloid precursors in BM, peripheral blood, and extramedullary tissues

CHRONIC MYELOGENOUS LEUKEMIA

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Condition wherein the peripheral blood exhibits leukocytosis with increased myeloid series, particularly the later maturation stages, often with increased eosinophils & basophils

CHRONIC MYELOGENOUS LEUKEMIA

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Leukocyte Alkaline Phosphatase (LAP) score of CML

Dramatically ↓

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enzyme found in membranes of secondary granules of neutrophils

Leukocyte Alkaline Phosphatase

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Stains ALP present in most neutrophil

Leukocyte Alkaline Phosphatase Stain (LAPS)

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Differentiate CML (↓) from leukemoid reaction or polycythemia vera

Leukocyte Alkaline Phosphatase Stain (LAPS)

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What is differentiated in Leukocyte Alkaline Phosphatase Stain (LAPS)?

CML
Leukemoid reaction or polycythemia vera

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How is the degree of reactivity measured in LAPS?

scoring each 100 neutrophils according to the amount of precipitated dye present

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Scoring of LAPS

0 (weak) – 4 (strong)

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Anticoagulant used for LAPS specimen?

What must NOT used? What is the result?

HEPARIN

EDTA: falsely ↓ LAPS

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Conditions with INCREASED LAPS

Leukemoid Reaction
Polycythemia Vera
3rd Trimester of Pregnancy

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Condition with DECREASED LAPS

CML

Condition that is BCR-ABL1 positive

CML

BM in this condition exhibits intense hypercellularity with myeloid precursor predominance

CML

Megakaryocytes in CML

normal to ↑

Can progress from chronic stable phase through an accelerated phase into transformation to acute leukemia (rapid progress and onset of symptoms)

CML

TREATMENTS FOR CML

BM Transplantation - preferred Tyrosine kinase inhibitor

targets abnormal BCR-ABL protein to block its function causing the CML cells to die

Tyrosine kinase inhibitor

Peripheral blood of this condition has immature basophils and neutrophils, micromegakaryocyte, spectrum of granulocytes, including multiple myelocytes, bands, and immature basophil

CML

He first described Polycythemia Vera as Polycythemia Rubra Vera

William Osler (1910)

Clinical description of Polycythemia vera according to William Osler (1910)

engorged veins plethora (face and palm swelling) ↑ RBC count leukocytosis thrombocythemia

He added PV to the classification of MPNs

Dameshek (1951)

Main differential diagnosis of Polycythemia Vera according to Dameshek (1951)

Reactive erythrocytosis due to hypoxia

Mechanism of hypoxia causing reactive erythropoiesis

Erythropoiesis is stimulated = ↑ RBC production = makes blood thicker than normal → blood clot and other complications

Clonal stem cell disorder characterized by hyperproliferation of erythroid, myeloid, and megakaryocytic lineages

POLYCYTHEMIA VERA

Lineages with hyperproliferation in Polycythemia vera

erythroid myeloid megakaryocytic

WHO Diagnostic Criteria for Polycythemia vera must meet?

3 major criteria and 1 minor criterion

MAJOR CRITERIA OF POLYCYTHEMIA VERA accdg. to WHO

Hemoglobin, Hematocrit, RBC mass (has assigned values) Bone marrow showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, megakaryocytic proliferation with pleomorphic, mature megakaryocytes (difference is size) Presence of JAK2V617F/JAK2 exon 12 mutation

PV Major criteria for hemoglobin (men & women)

Hemoglobin (men): >16.5 g/dL Hemoglobin (women): >16.0 g/dL

PV Major criteria for hematocrit (men & women)

Hematocrit (men): >49% Hematocrit (women): >48%

PV Major criteria for RBC mass

↑ RBC mass mean normal

protein important for controlling the hematopoietic stem cells production of blood cells

Janus kinase (JAK)

switch of valine (V) to phenylalanine (F) at position 617 (changes the shape of JAK2 protein)

JAK2V617F

PV Minor criterion

Subnormal serum EPO level

Additional diagnostic features of PV

1) Arterial oxygen saturation of 92% (normal) or greater and splenomegaly 2) Thrombocytosis: > 400x10^9 platelets/L 3) Leukocytosis: >12x10^9cells/L w/o fever/ infection 4) ↑ LAP, serum vitamin B12, or unbound vitamin B12 binding capacity

Arterial oxygen saturation of PV

92% (normal) or greater

Platelet count of PV

> 400x10^9 platelets/L (thrombocytosis)

WBC count of PV

>12x10^9cells/L (leukocytosis) *w/o fever / infection

LAP, serum vitamin B12, or unbound vitamin B12 binding capacity of PV

↑

Clinical S/S of PV

Hallmark: Plethora hyperviscosity hypertension (50% of pt) – Headache – Weakness – Pruritis - ↑ blood histamine – Weight loss – Fatigue 1/2 of PV pt. – thrombocytosis 1/3 of PV pt. – thrombotic/hemorrhagic episodes

Hyperviscosity in PV is due to?

↑ RBC mass

Hypertension in PV is due to?

HCT >60%

Presenting symptoms associated with hyperviscosity and hyperproliferation

Headache Weakness Pruritis Weight loss Fatigue

Hallmark of PV

Plethora

Associated with ↑ blood histamine and is often not associated with a visible rash in PV patients

Pruritis

Thrombocytosis are found in ____ of patients

1/2

Thrombotic/hemorrhagic episodes are found in ____ of patients

1/3

Increased laboratory tests in PV

RBC count Packed cell volume (HCT) Hemoglobin

Normal laboratory test in PV

RBC indices

Decreased laboratory test in PV

Serum erythropoietin (RBC proliferation is independent of endogenous EPO)

All of these values are considered as? 20.6 g/dL Hemoglobin 80% Microhematocrit 28,000 × 10^9/L Total leukocyte (WBC) count 1,400 × 10^9/L Platelet count

Peak polycythemic values

Peak polycythemic values in hemoglobin

20.6 g/dL

Peak polycythemic values in microhematocrit

80%

Peak polycythemic values in total leukocyte (WBC) count

28,000 × 10^9/L

Peak polycythemic values in platelet count

1,400 × 10^9/L

TREATMENTS FOR PV

Therapeutic phlebotomy Myelosuppressive therapy Targeted molecular therapy

A treatment for PV wherein there is a controlled removal of large blood volume to reduce blood volume, red cell mass and iron stores

Therapeutic phlebotomy

A treatment for PV for suppressing RBC overproduction

Myelosuppressive therapy

A treatment for PV wherein molecules targeted is JAK2 mutation

Targeted molecular therapy

aka ESSENTIAL THROMBOCYTOSIS

Essential thrombocytemia Primary thrombocytosis Idiopathic thrombocytosis Hemorrhagic thrombocythaemia

Condition with significant increase in circulating platelets, in excess of 1,000 × 10^9/L

ESSENTIAL THROMBOCYTOSIS/ ESSENTIAL THROMBOCYTHEMIA

Circulating platelets in essential thrombocytosis is in excess value of

1,000 × 10^9/L

WHO criteria required for essential thrombocytosis diagnosis

sustained thrombocytosis with a platelet count of > or equal to 400 x 10^9/L

↑ platelet counts may be encountered as a reactive phenomenon, secondary to a variety of systemic conditions, or essential thrombocythemia, a BM primary disorder

essential thrombocytosis

MAJOR CRITERIA OF ESSENTIAL THROMBOCYTOSIS/ ESSENTIAL THROMBOCYTHEMIA

1. Megakaryocyte proliferation with large and mature morphology, little to no granulocyte or erythroid proliferation 2. Rarely, minor (grade 1) increase in reticulin fibers 3. Must not meet any criteria for BCR-ABL1-positive CML, PV, PMF, MDS or other myeloid neoplasms 4. JAK2 V617F, CALR, or MPL mutations

reticulin fibers level in essential thrombocytosis

Rarely, minor (grade 1) increase

Mutations in essential thrombocytosis

JAK2 V617F, CALR, or MPL mutations

MINOR CRITERION OF ESSENTIAL THROMBOCYTOSIS/ ESSENTIAL THROMBOCYTHEMIA

Presence of a clonal marker OR Absence of evidence of reactive thrombocytosis

Describe platelets of patient with essential thrombocytosis

Appear normal Giant bizarre platelets Platelet aggregates Micromegakaryocytes Megakaryocyte fragments

Describe erythrocytes of patient with essential thrombocytosis

Normocytic and normochromic, unless iron deficiency is present secondary to excessive bleeding

Splenic infarction in patient with essential thrombocytosis has a PBS inclusions and appearance such as?

* Howell-Jolly bodies * Nucleated RBCs * Poikilocytosis

TREATMENT FOR ET

plateletpheresis – quickly reduce platelet ct. reduce platelet count and control thrombosis

similar to blood donation but with apheresis machine which returns blood in cycle

plateletpheresis

results when primary myelofibrosis progeny cells stimulate BM fibroblasts to secrete excessive collagen

PRIMARY MYELOFIBROSIS

nucleated RBC (normoblasts) and myelocytes are released into the circulation (leukoerythroblastosis) when there is extramedullary hematopoiesis (ie, non-marrow organs) have taken over blood cell production because of fibrosed marrow

PRIMARY MYELOFIBROSIS

disrupts normal BM architecture and replaces hematopoietic tissue resulting in pancytopenia

collagen overproduction

what is in excess in primary myelofibrosis

collagen

collagen overproduction disrupts normal BM architecture and replaces hematopoietic tissue leading to?

pancytopenia (decreased production in all cell types) *followed by secondary hematopoietic tissue production of cells

process where nucleated RBC (normoblasts) and myelocytes are released into the circulation

leukoerythroblastosis

MAJOR CRITERIA OF PRIMARY MYELOFIBROSIS

1. Megakaryocytic proliferation with abnormal morphology, usually accompanied by reticulin and/or collagen fibrosis 2. Not meeting the criteria for other MPNs 3. Evidence of JAK2V617F or other related mutations

MINOR CRITERIA OF PRIMARY MYELOFIBROSIS

1. Leukoerythroblastosis (presence of nucleated red cells and immature white cells) 2. Anemia 3. Increased serum lactic dehydrogenase (LDH) levels 4. Splenomegaly

presence of nucleated red cells and immature white cells

Leukoerythroblastosis

Describe Prefibrotic stage of PMF

* Markedly hypercellular BM * Dysmegakaryopoiesis * Megakaryocytes are morphologically abnormal with bizarre hyperchromatic nuclei (arrow) --> key to PMF recognition

key to PMF recognition

Megakaryocytes are morphologically abnormal with bizarre hyperchromatic nuclei