CLINICAL PATHOLOGY

WHITE BLOOD CELL DISORDERS (EXTRA TOPICS)

First Shift: August 21, 2018

o Ex: Mutated JAK2 in Polycythemia Vera

TABLE OF CONTENTS

II. POLYCYTHEMIA VERA

I. Myeloproliferative Neoplasm………………….…………………………...…. 1
II. Polycythemia Vera………………………………………………………………… 1
 Increased Hemoglobin/ hematocrit above the upper limit of
III. Essential Thrombocythemia………..…………………………….………….. 2 normal for the patient’s age and sex
IV. Myelofibrosis ………………………………………………………….…………… 2  A clonal stem cell disorder with trilineage myeloid
involvement.
 Characterized by growth factor independent erythroid
I. MYELOPROLIFERATIVE NEOPLASM proliferation resulting to markedly increased red cell mass.
Myeloproliferative Neoplasms (MPNs) are blood cancers that  Rule out all causes of high red cells before PV
occur when the body makes too many white or red blood cells,  JAK 2 mutation is present in over 95% of Patients
or platelets.
A mutation of a particular gene (a segment of DNA that ABSOLUTE VS RELATIVE
makes proteins) known as Janus kinase 2 (JAK2) is found in a  Absolute: Red Cell Mass > 125% of that expected for body
large proportion of people with MPNs. The exact meaning of this mass and gender
mutation remains unclear but it appears to play a role in the o Primary - enhanced response of erythroid progenitor
overproduction of blood cells seen in these disorders. cells to cytokines
o Secondary - driven by factors outside erythroid
CLASSIFICATIONS compartment
 Leukemic MPNs (BCR-ABL Positive)  Erythropoietin mediated:
o Myelogenous Leukemia: Prototype of MPNs  Central hypoxia
 Non-Leukemic MPNs (BCR-ABL Negative)  Chronic lung disease
o Polycythemia Vera: Increase red cells, Increase Hct  R to L heart shunts
o Essential Thrombocythemia: Increase PL  CO poisoning
o Primary Myelofibrosis: Increase bone marrow fibrosis  Smoking
 Obstructive sleep apnea
COMMON FEATURES OF MPNs  High altitude
o Originate from a multipotent progenitor cell  Drug associated
o Relatively normal cellular proliferation  EPO administration
o A tendency to evolve into each other or to myelofibrosis  Androgen administration
o Phenotypic and genotypic mimicry  Local Hypoxia
o Abnormal response to cytokines: hypersensitivity to numerous  Renal artery stenosis
growth factors  Hydronephrosis
o Similar genetic mutation: JAK2 gene & MPL gene  Renal cysts (polycystic kidney disease)
 Post-renal transplant erythropoiesis
JAK-STAT SIGNALLING PATHWAY  Pathologic EPO production
Transmits information from outside the cell through the cell  Tumors: Hepatoma, Renal cell CA, Meningioma,
membrane and into the gene promoters on the DNA inside the etc
nucleus  Relative or pseudopolycythemia: red cell volume is normal
3 Components: but plasma volume is decreased
1. Receptor (Cytokine/ Growth Factor Receptor)
2. JANUS Kinase (JAK) DIAGNOSTIC CRITERIA BY PV STUDY GROUP
-receptor Tyrosine Kinase that is essential for  Major:
growth factor signalling o A1 Raised RCM: Males >/= 36ml/kg Females >/=
3. Signal Transducer and Activator of Transcription 32ml/kg
(STAT) o A2 Normal O2 Satn >92%
o A3 Splenomegaly
NORMAL JAK2 VS. MUTATED JAK2  Minor:
 Normal: Growth factor will attach to tyrosine kinase o B1 PC >400 x109/L
receptor then activating downstream reaction o B2 WBC count >12 x 109/L
o No growth factor attaching: No growth o B3 LAP score >100
 JAK2 mutation: Constantly activated, nonstop o B4 Serum B12 >900 pg/L or unbound B12 binding
proliferation of myeloid cells/WBC/RBC (depending on cell capacity > 200 pg/L
involved)  Diagnosis: A1+A2+A3 or A1 + A2 + 2 of minor
Abe Ruiz, Socorro Suganob, Arienne Sumague, and Bien Romulo| 1
 2. Bone marrow biopsy with proliferation mainly of
WHO DIAGNOSTIC CRITERIA FOR PV megakaryocytic lineage with increase enlarged mature
 Major criteria: megakaryocyte
o Hemoglobin (Men) >18.5 g/dL; (Women) 16.5 g/dL a. No significant increase or left shift of neutrophil
o Presence of JAK2 V617F or other functionally similar granulopoiesis or erythropoiesis
mutation such as JAK2 exon 12 mutation 3. Not meeting WHO criteria for PV, PMF, BCR-ABL1-positive-
 Minor criteria: CML or MDS, or other myeloid neoplasm
o Bone marrow biopsy showing hypercellularity for age 4. Demonstration of JAK2 V617F or other clonal marker; if
with trilineage growth (panmyelosis) with prominent absent JAK2 V617F, no evidence for reactive thrombocytosis
erythroid, granulocytic, and megakaryocytic proliferation
o Serum erythropoietin level below reference range MANAGEMENT
o Endogenous erythroid colony formation in vitro  Goal: reduce risk of thrombosis or hemorrhage
 Diagnosis Requirement: 1. Modification of cardiovascular risk factors
o Presence of both Major criteria and 1 minor criterion 2. Antiplatelet therapy
o Or presence of 1st major criteria together with 2 minor 3. Cytoreductive therapy
criteria
RISK FACTORS FOR COMPLICATIONS IN ET
WHO DIAGNOSTIC CRITERIA FOR PV Age >60 yrs.
 Increased Hb, Hct, RBC count, Total RCV is increased Prior thrombosis
 Neutrophilic leukocytosis, basophilia Cardiovascular risk
Thrombosis
 Increased platelet count Leukocytosis
Marrow fibrosis
 JAK 2 mutation
JAK2 V617F mutation
 Hypercellular bone marrow with panmyelosis
 Decreased EPO Hemorrhage Marrow fibrosis
 Increased Urate Disease duration
Myelofibrotic
Anagrelide theraphy
Transformation
CLINICAL FEATURES Marrow fibrosis
Disease duration
Result of Hyperviscosity, Hypervolemia, Hypermetabolism
Acute Myeloid Leukemia Genotoxic therapy
 Headaches, dyspnea, blurred vision and night sweats,
Use of >1 cytoreductive agent
pruritus after a hot bath
 Plethora-ruddy cyanosis, conjunctival suffusion, retinal
venous engorgement IV. MYELOFIBROSIS
 Splenomegaly in 75% of patients  Primary myelofibrosis: clonal disease characterized by
 Hemorrhage and Thrombosis progressive generalized reactive marrow fibrosis with
 Hypertension extramedullary hematopoiesis in the liver and spleen
 Gout/Hyperuricemia (Myelofibrosis with myeloid metaplasia)
o Chronic, progressive clonal panmyelosis characterized
PROGNOSIS
by megakaryocytic and often granulocytic hyperplasia
 Good
with varying degrees of reactive fibrosis of the
 Median survival: 10-16 years
 Thrombosis and hemorrhage are major causes of morbidity marrow and extramedullary hematopoiesis
and mortality
 30% transform to MF “spent phase”  Postpolycythemic myelofibrosis/ Posthrombocythemic
 5% to acute leukemia (may be affected by treatment) myelofibrosis or Myeloid metaplasia

III. ESSENTIAL THROMBOCYTHEMIA Characteristic findings in Myelofibrosis

 Persistent platelet count of > 450 x 109/L  Anemia
o Rule out all causes of high platelets before ET  Splenomegaly
 Due to megakaryocyte proliferation and overproduction  Osteosclerosis
platelets
 Diagnosis by exclusion but presence of JAK2 mutation assay
 Peripheral Blood Smear: Leukoerythroblastic anemia
= positive diagnosis
o Immature granulocytes, Erythroblasts
WHO CRITERIA FOR ET: (DIAGNOSIS REQUIRES ALL) (leukorythroblastosis)
1. Sustained PLT count >450 x 109/L o Tear drop shaped red cells (dacryocytes)

Abe Ruiz, Socorro Suganob, Arienne Sumague, and Bien Romulo)| 2

  Mainly due to squeezing of RBC through the tight
fibrosis in the Bone Marrow

 Bone Marrow Biopsy

o Normal: Combination of inflammatory cells and Fats
 Cellularity in Marrow: Percentage of cell vs fat
 Eg: 50% Cells

o Essential Thrombocythemia: Marrow Fibrosis

 Nonfunctional
 Pancytopenia
 Stains black in Reticulin stain (scanty collagen,
abundant reticulin fibers)

Clinical features
 Occurs typically in persons over 50 years of age
 Asymptomatic at presentation: 1/3
 Symptoms:
o Symptoms of anemia
o Abdominal discomfort (due to enlarged spleen)
o Early satiety
o Weight loss
o Constitutional symptoms: fever and night sweats
 Physical findings
o Splenomegaly (due to extramedullary hematopoiesis)
o Hepatomegaly
o Jaundice

WHO Diagnostic Criteria for Primary Myelofibrosis

 Diagnosis requires meeting all three (3) major criteria
and two (2) minor criteria

Abe Ruiz, Socorro Suganob, Arienne Sumague, and Bien Romulo)| 3