Chronic Neutrophilic Leukemia

Question 1

What is the definition of CNL ?

Answer 1

• rare MPN
• characterized by sustained peripheral blood neutrophilia, bone marrow hypercellularity due to neutrophilic predominance and hepatosplenomegaly
• NO Ph chromosome
  
  • no BCR-ABL fusion gene
• IMP
  
  • diagnosis requires the exclusion of reactive neutrophilia, MPN/MDS overlap and other MPNs

Question 2

What is the epidemiology of CNL ?

Answer 2

• true incidence of this entity is unknown
  
  • > 200 cases have been reported
• generally affects older adults
  
  • rarely reported in adolescents and young adults

Question 3

What is the etiology of CNL ?

Answer 3

• the true cause of CNL is unknown
• some cases have occurred following cytotoxic therapy
• do not confuse with a neutrophilic leukamoid reaction:
  
  • can be see with other neoplasms including:
    
    • multiple myeloma
    • MGUS
    • other neoplasms
    • result from increase in G-CSF

Question 4

What is the localization and clinical

features of CNL ?

Answer 4

• the peripheral blood and bone marrow are always involved
• spleen and liver usually show leukemic infiltrates
• Note:
  
  • any tissue can be infiltrated
• The most consistent clinical finding: splenomegaly as well as hepatomegaly
• 30% of cases report mucosal bleeding
  
  • including the GI tract
  • gout and pruritis are also possible features
  • serum Vitamin B12 levels and uric acid are often elevated

Question 5

What are the microscopic findings

of the peripheral blood in CNL ?

Answer 5

• peripheral blood show neutrophilia with a WBC > 25 x 10^9/L
• neutrophils are normally segmented but bands can be see
• IMP
  
  • neutrophil precursors (Promyelocytes, myelocytes, and metamyelocytes) account for < 5%, but rarely can be up to 10%
  • myeloblasts are never observed in the peripheral blood
• Neutrophils
  
  • frequently show toxic granules and Dohle bodies
    
    • IMP: these features are non-specific and can be seen in leukamoid reactions
  • but can also appear normal
  • no dysplasia
• Erythroids and platelets appear normal

Question 6

What are the microscopic findings

of CNL in the bone marrow ?

Answer 6

• hypercellular bone marrow with neutrophilic proliferation
• M:E ratio may be > 20:1
• proportion of myelocytes and neutrophils is increased (blasts and pros are not)
• IMP:
  
  • erythrocyte and megakaryocyte proliferation may increase
  • megas may be cytologically normal or increased small, hypolobated forms can be seen
• IMP:
  
  • significant dysplasia in the lineages should not be seen
  • if it is seen a diagnosis of atypical CML may be considered
• reticulin fibrosis is uncommon

Question 7

What is important to remember when

increased neutrophils are present ?

Answer 7

• there is an increased frequency with plasma cell neoplasms and MGUS to produce a neutrophilic leukamoid reaction.
• therefore, imp to look for atypical plasma cells in the bone marrow

Question 8

Where is the infiltrate seen in the

spleen and liver ?

Answer 8

• spleen
  
  • mostly in the red pulp
• Liver
  
  • affects the sinusoids, portal areas or both

Question 9

What is an important malignant

differential diagnostic consideration for CNL ?

Answer 9

• neutrophilic variant of CML

Question 10

What is the cell of origin in CNL ?

Answer 10

• hematopoietic stem cell which may have limited lineage potential

Question 11

What are the cytogenetics of

CNL ?

Answer 11

• cytogenetics are usually normal but there may be evolution of the clone over the course of the disease
• del20(q)
  
  • most common cytogenetic abnormality

IMP: there is NO BCR-ABL1 fusion

• must rule out the neutrophilic variant of CML

Question 12

What mutation is known to be strongly

associated with CNL?

Answer 12

• CSF3R mutation
• often seen together with either:
  
  • SETBP1
  • or
  • ASXL1 (if present portends a worse prognosis)

Question 13

What other mutation has been

reported in at least a dozen patients?

Answer 13

• JAK2V617F
  
  • sometimes is a homozygous mutation
  • appears to be an alternate mechanism for leukemogenesis

Question 14

What are the prognostic and predictive factors ?

Answer 14

• generally thought to be a slow and progressive disease but there is variable prognosis
  
  • 6 months to >20 years
• neutrophilis is usually progressive and anemia and thrombocytopenia may follow
  
  • may transform to MDS and AML