Polycythemia Vera

Question 1

What is the definition of

PV ?

Answer 1

• chronic MPN characterized by increased RBC production independent of the mechanisms that normally regulate it
• JAK2 V617F mutation virtually in all patients
  
  • or another functionally similar JAK2 mutation
• Proliferation:
  
  • erythroid lineage
  • granulocytes and megkaryocytes
  • aka Panmyelosis

Question 2

What two phases of PV can be seen ?

Answer 2

• polycythemic phase
  
  • associated with elevated hemoglobin levels, elevated hematocrit, and increased RBC mass
• spent phase
  
  • post-polycythemic myelofibrosis
  • develop cytopenias (anemia)
  • extramedullary hematopoiesis and hypersplenism due to bone marrow fibrosis

Question 3

What does the natural progression

of PV include ?

Answer 3

• myelofibrosis
• low incidence of evolution to MDS and or Leukemia

Question 4

What must be excluded to make

the diagnosis of PV?

Answer 4

• all secondary causes of erythrocytosis
• heritable polycythemia
• other MPNs

Question 5

What is the epidemiology of PV ?

Answer 5

• incidence increases with age
  
  • lowest rates in Japan and Israel
• most reports indicate a slight male predominance
• median patient age: 60 years
  
  • < 20 years of age, rare reports

Question 6

What is the etiology of PV ?

Answer 6

• underlying cause is unknown in most cases
• genetic predisposition in some families is seen
• Suggested possible causes include:
  
  • ionizing radiation
  • occupational exposure to toxins

Question 7

What is the localization of

PV ?

Answer 7

• blood and bone marrow are the major sites of involvement
• spleen and liver can also be affected
  
  • these are the major sites of extramedullary hematopoiesis
• but any organ can be damaged due to vascular consequences of increased RBC mass

Question 8

What are the criteria required

for the diagnosis of PV ?

Answer 8

• requires that either all 3 major criteria OR the first 2 major criteria plus the minor criteria be true

Question 9

What are the major criteria for PV ?

Answer 9

• elevated Hgb concentration (> 16.5 g/dL in men, >16 g/dL in women) or elevated hematocrit (>49% in men, >48% in women) or Increased red blood cell mass (>25% above mean normal predicted value)
• bone marrow biopsy showing age-adjusted hypercellularity with trilineage growth (panmyelosis)
  
  • includes erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
• Presence of JAK2V617F or JAK2 exon 12 mutation

Question 10

What is the minor criterion for

PV ?

Answer 10

• subnormal serum erythropoietin level

Question 11

What are the clinical features

of PV ?

Answer 11

• the major symptoms are associated with hypertension or vascular abnormalities due to the increased RBC mass
  
  • 20% of cases can have thrombosis (venous or arterial), MI, or other ischemic event be the first presenting symptom
• IMP
  
  • mesenteric, splenic, or portal or Budd-Chiari syndrome should lead to a suspicion of PV
• Other symptoms
  
  • blurry vision, headache, dizziness, parasthesias
  • pruritis, gout

Question 12

What are some of the physical

findings in PV ?

Answer 12

• plethora
• palpable splenomegaly
• sometimes hepatomegaly

Question 13

What are the microscopic features

of peripheral blood in PV ?

Answer 13

• mild to overt excess of normochromic RBCs
• Note:
  
  • if there is iron deficiency due to bleeding the RBCs may be hypochromic and microcytic
• Neutrophilia and basophilia may be rarely present
• occasional immature granulocytes can be seen

Question 14

What are the microscopic findings of

PV in the bone marrow ?

Answer 14

• cellularity is usually increased
  
  • hypercellularity is especially noticeable in the subcortical marrow space
  • panmyelosis accounts for the increased cellularity but increased erythroid and megakaryocytes are most prominent
    
    • erythropoiesis is usually normoblastic (left shifted) with large islands of cells
• myeloblast proportions are not increased
• megakaryocytes are increased with frequently hypersegmented nuclei
  
  • tend to form loose clusters, lie close to bony trabeculae
  • also display significant pleomorphism

Question 15

At the beginning, which disease

entity can PV mimic ?

Answer 15

• essential thrombocythemia

Question 16

What is the morphology that can help

point away from ET and towards PV ?

Answer 16

• marrow sinuses are dilated and often filled with erythrocytes
• plus the panmyelosis

Question 17

What must be done in order

to diagnose PV ?

Answer 17

• bone marrow biopsy with morphologic evaluation is essential in the diagnosis of PV

Question 18

What is the reticulin deposition

in a case of PV ?

Answer 18

• generally see normal reticulin staining in about 80% of cases
• but other cases have mild to moderate with even collagen fibrosis

Note: cases with a minor increase in reticulin (WHO grade 1) have been associated with more rapid progression to post-PV myelofibrosis

Question 19

What are two other findings in the bone marrow

of PV patients that are typically seen ?

Answer 19

• 20% of cases have reactive lymphoid aggregates
• >95% of cases have no stainable iron on the aspirate or biopsy

Question 20

What is the most common pattern of disease

progression for PV and how does it present?

Answer 20

• post-PV myelofibrosis
• during later phases, erythropoiesis progressively decreases, RBC mass normalizes then decreases and the spleen further enlarges
• persistent leukocytosis occurs around the time of progression
  
  • associated with more aggressive disease course
• these changes are usually accompanied with bone marrow changes as well

Question 21

What are the bone marrow findings

in progression of PV (post-PV MF) ?

Answer 21

• myeloid metaplasia
  
  • leads to leukoerythroblastic peripheral blood smear, poikilocytosis with dacrocytes
• splenomegaly due to extramedullary hematopoiesis
• overt reticulin and collagent fibrosis
• cellularity varies but specimens can be hypocellular
• clusters of megakaryocytes, some with very hyperchromatic nuclei, are prominent
• erythropoiesis and megakaryopoiesis are decreased
• RBCs, granulocytes and megas are sometimes found lying within dilated marrow sinusoids

Question 22

What features are usually not seen

in the post-PV myelofibrosis ?

Answer 22

• >10% blasts in the peripheral blood or
• presence of substantial myelodysplasia is unusual

If these findings are present they likely represent transformation to an accelerated phase

Question 23

What are cases of PV with >20% blasts called ?

Answer 23

• if there are >20% blasts they are considered the blast-phase of post-PV MF
  
  • formerly called AML

Question 24

What is the postulated cell of origin ?

Answer 24

• hematopoietic stem cell

Question 25

What is the most common genetic abnormality in PV ?

Answer 25

* somatic gain of function mutation JAK2 V617F * it occurs in \>95% of cases but is not specific for this entity * Note: \<5% of cases of AML, MDS, CML can have this abnormality as well * rare cases of JAK2-mutant PV acquire a BCR-ABL1 rearrangement * but the significance of this is uncertain * however, a phenotypic and morphologic shift to a CML picture can occur

Question 26

What is the other JAK2 mutation and it's morphologic findings?

Answer 26

* mutations in exon 12 of JAK2 * found in 3% of cases * predominance of erythroids

Question 27

What are the cytogenetics of PV ?

Answer 27

* at diagnosis, cytogenetic abnormalities are detectable in as as many as 20% of cases * most common recurrent cytogenetic aberrations: * gain of chromosome 8 or 9 * del20(q) * del13(q) * del 9(p) * gains of chromosomes 8 and 9 sometimes seen together * chromosome abnormalities increase with disease progression * if they progress to AML * cytogenetics are often similar to those seen in therapy related AML

Question 28

What are the prognostic and predictive factors associated with PV?

Answer 28

* with current treatment, median survival times. \>10 years * prognostic factors other than older age remain controversial * leukocytosis * abnormal karyotype * most patients die from thrombotic complications or secondary malignancies * 20% succumb to MDS / AML