Primary Myelofibrosis

Question 1

What is the definition of PMF ?

Answer 1

• clonal proliferation of predominantly abnormal megakaryocytes and granulocytes in the bone marrow
  
  • at advanced stages it can progress to dense fibrosis and extramedullary hematopoiesis
• Fibrotic stage
  
  • leukoerythroblastosis
  • hepatomegaly
  • splenomegaly

Question 2

What is the epidemiology of

PMF ?

Answer 2

• not super common but also not rare
• 30-50% account for the pre-fibrotic PMF
• men and women are affected the same
  
  • usually 6-7th decade
• only ~10% of overt PMF cases are diagnosed in younger patients <40

Question 3

What is the possible etiology of PMF ?

Answer 3

• benzene or ionizing radiation exposure has been documented in some cases
• rare familial cases of young kids with bone marrow fibrosis
  
  • some appear to be an autosomal recessive condition

Question 4

What is the localization of PMF ?

Answer 4

• blood and bone marrow are always involved
• extramedullary hematopoiesis (myeloid metaplasia)
  
  • prominant particularly in the spleen which harbors neoplastic stem cells
  • other sites: liver, LN, kidney, renal glands, dura mater, skin, soft tissue
• increase in circulating CD34+ cells in later stages of the disease
  
  • IMP: this is particularly seen in overt PMF

Question 5

What are the clinical features of PMF ?

Answer 5

• 30% of cases are asymptomatic at diagnosis
  
  • discovered due to splenomegaly
• CBC
  
  • anemia
  • leukocytosis and/or thrombocytosis
• leukoerythroblastosis on PB or increased LDH
• in pre-fibrotic PMF
  
  • only finding may be thrombocytosis
  • can mimic ET

Question 6

Why is a bone marrow biopsy

essential for the diagnosis of PMF ?

Answer 6

• because clinically the patients can present as ET
  
  • only thrombocytosis and nothing else
• but it is important to differentiate them because management is different

Question 7

What symptoms do >50% of patients

with PMF experience ?

Answer 7

• constitutional symptoms
  
  • fatigue, dyspnea, weight loss
  • night sweats
  • low-grade fever
  • cachexia
• Gouty arthritis and renal stones can also occur due to hyperurecemia

Question 8

What mutations when present help

distinguish PMF from reactive conditions ?

Answer 8

• JAK2V617F found in 50-60% of early stage cases
• CALR mutations 24%
• MPL mutations 8%
• Triple negative 12% of cases

IMP: these mutations are not specific to PMF, can be seen in ET and PV

Question 9

What are the microscopic findings

of fibrotic PMF ?

Answer 9

• hypocellular, fibrotic marrow, osteosclerosis with megakaryocytic proliferation
• extramedullary hematopoiesis
• PB
  
  • leukoerythroblastosis
  • tear drop cells

Question 10

What are the pre-fibrotic findings

in PMF ?

Answer 10

• hypercellular bone marrow
• increase in number of neutrophils and megakaryocytes
  
  • mild left shift in granulocytes but mature forms predominate
  • myeloblasts are not increased in percentage but overall may be more due to the cellularity
• decreased erythropoiesis with no significant dysplasia
• megas are abnormal
  
  • abnormal localization adjacent to bone marrow vascular sinuses and trabeculae

Question 11

What is the range of morphology

for the megakaryocytes in PMF ?

Answer 11

• most megas are large with atypical, hyperchromatic nuclei
  
  • can see small megas
  • abnormal N:C ratios
  • abnormal pattern of chromatin clumping
    
    • hyperchromatic and bulbous forms
    • cloud like or balloon shaped
• frequent naked/bare megakaryocytic nuclei are often seen

Question 12

What other unsual things can be

seen in PMF bone marrows ?

Answer 12

• vascular proliferation (although usually mild)
• lymphoid nodules are seen 20% of cases

Question 13

What are some morphologic findings of

overtly fibrotic PMF ?

Answer 13

• bone marrow is hypocelllular with some areas of cellularity
• blasts may be increased but should be <10%
• atypical megakaryocytes are conspicuous and adjacent to dilated vascular sinuses
  
  • intrasinusoidal hematopiesis is a finding often associated with marrow fibrosis
• osteoslcerosis with new bone apposition

Question 14

What can indicate progression in PMF ?

Answer 14

• bone marrow fibrosis
• development of a monocytosis
• blasts in the peripheral blood (10-19%)
• blasts with clustering and increase in number in the bone marrow
  
  • >20% blasts indicates blast transformation

Question 15

What is the genetic profile of

PMF ?

Answer 15

• nothing is specific for PMF
• 50-60% of cases JAK2V617F
• 30% CALR
  
  • IMP: favorable impact on survival
• 8% MPL
• 12% of cases are triple negative

note: occasionally cases can acquire a BCR-ABL rearrangement (not FUSION), but significance of this is uncertain

Question 16

What cytogenetic abnormalities

have been identified in PMF ?

Answer 16

• cytogenetic abnormalities can occur in 30% of cases
• no philadelphia chromosome is present at diagnosis
• presence of del13 or der(6)t(1;6)
  
  • strongly suggestive of PMF
• most common
  
  • del 20q
  • partial trisomy 1q
  • gains of chromosome 8 and 9

Question 17

What are the prognostic and predictive

markers of PMF ?

Answer 17

• time of survival ranges from months to years
  
  • depends on degree of fibrosis at diagnosis
  • over fibrosis 3-7 years
  • pre-fibrotic stage 10-15 years

Question 18

What are the predictors of inferior

survival in PMF ?

Answer 18

• age > 65
• hemoglobin < 10 g/dL
• leukocytes >25 x10^9/L
• circulating blasts > 1%
• constitutional symptoms
• transfusion dependence
• platelet count <100
• unfavorable karyotype
  
  • complex karotype
  • gain of chromosome 8, loss of chromsome 7/7q, isochromosome 17p, inversion 3q, loss of 5q or 12p or 11p23.3 rearrangement

Question 19

What is a mutation defined poor prognostic

factor?

Answer 19

• high risk disease
  
  • CALR-negative and ASXL1 positive mutation status

Question 20

What are major causes of morbidity

and mortality?

Answer 20

• bone marrow failure (infection, hemorrhage)
• thromboembolic events
• portal hypertension
• cardiac failure
• secondary AML
  
  • occurs in 5-30% of cases