Polycythemia Vera Flashcards
What is the definition of
PV ?
- 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
What two phases of PV can be seen ?
- 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
What does the natural progression
of PV include ?
- myelofibrosis
- low incidence of evolution to MDS and or Leukemia
What must be excluded to make
the diagnosis of PV?
- all secondary causes of erythrocytosis
- heritable polycythemia
- other MPNs
What is the epidemiology of PV ?
- 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
What is the etiology of PV ?
- underlying cause is unknown in most cases
- genetic predisposition in some families is seen
- Suggested possible causes include:
- ionizing radiation
- occupational exposure to toxins
What is the localization of
PV ?
- 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
What are the criteria required
for the diagnosis of PV ?
- requires that either all 3 major criteria OR the first 2 major criteria plus the minor criteria be true
What are the major criteria for PV ?
- 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
What is the minor criterion for
PV ?
- subnormal serum erythropoietin level
What are the clinical features
of PV ?
- 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
What are some of the physical
findings in PV ?
- plethora
- palpable splenomegaly
- sometimes hepatomegaly
What are the microscopic features
of peripheral blood in PV ?
- 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
What are the microscopic findings of
PV in the bone marrow ?
- 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
At the beginning, which disease
entity can PV mimic ?
- essential thrombocythemia
What is the morphology that can help
point away from ET and towards PV ?
- marrow sinuses are dilated and often filled with erythrocytes
- plus the panmyelosis
What must be done in order
to diagnose PV ?
- bone marrow biopsy with morphologic evaluation is essential in the diagnosis of PV
What is the reticulin deposition
in a case of PV ?
- 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
What are two other findings in the bone marrow
of PV patients that are typically seen ?
- 20% of cases have reactive lymphoid aggregates
- >95% of cases have no stainable iron on the aspirate or biopsy
What is the most common pattern of disease
progression for PV and how does it present?
- 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
What are the bone marrow findings
in progression of PV (post-PV MF) ?
- 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
What features are usually not seen
in the post-PV myelofibrosis ?
- >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
What are cases of PV with >20% blasts called ?
- if there are >20% blasts they are considered the blast-phase of post-PV MF
- formerly called AML
What is the postulated cell of origin ?
- hematopoietic stem cell
What is the most common genetic
abnormality in PV ?
- 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
- but the significance of this is uncertain
What is the other JAK2 mutation
and it’s morphologic findings?
- mutations in exon 12 of JAK2
- found in 3% of cases
- predominance of erythroids
What are the cytogenetics of PV ?
- 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
What are the prognostic and
predictive factors associated with PV?
- 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
