Chronic Lymphoproliferative Disorder of NK Cells and Aggressive NK cell Leukemia

Question 1

What is the definition of

Chronic Lymphoproliferative disorder of NK cells

(CLPD-NK) ?

Answer 1

• provisional entity
• rare and heterogeneous
• persistent > 6 months increase in peripheral blood NK cells
  
  • usually > 2 x 10^ 9/L
  • without a clearly identified cause
• difficult to differentiate between reactive and neoplastic conditions

Question 2

What is the epidemiology of

CLPD-NK ?

Answer 2

• predominantly occurs in adults
• median patient age is 60
• no racial or genetic predisposition

Question 3

What is the etiology of

CLPD-NK ?

Answer 3

• transient increases in NK cells can be seen in a variety of disorders
  
  • autoimmune conditions
  • viral infections
  • post bone marrow transplant and chemotherapy
• NK stimulation due to an unknown stimulus is the possible cause of increased NK cells
  
  • selects for and expands the clones

Question 4

What drug can cause

increases in NK cells ?

Answer 4

• TKI Dasatinib
  
  • produces a sustained increase in NK cells that can be monoclonal
• 1/3 of cases can have STAT3 mutations in the SH2 domain

Question 5

What is the localization of

CLPD-NK ?

Answer 5

• peripheral blood and bone marrow

Question 6

What are the clinical features of

CLPD-NK ?

Answer 6

• most patients are asymptomatic
• some may present with systemic symptoms and cytopenias
  
  • mainly neutropenia and anemia
  • lymphadenopathy, hepatomegaly and cutaneous lesions are uncommon
• Other conditions that NK cells can be increased with:
  
  • solid and hematological malignancies
  • vasculitis
  • splenectomy
  • neuropathy
  • autoimmune disorders

Question 7

CLPD-NK cells is not the same

as what other described entity ?

Answer 7

• NK cell lymphoproliferative disorders involving the GI tract
  
  • this entity is called:
    
    • NK-cell enteropathy or lymphomatoid gastropathy of NK-cell type

Question 8

What are the microscopic findings

of CLPD-NK ?

Answer 8

• usually lymphocytes are intermediate in size with round nuclei, condensed chromatin, moderate amounts of slightly basophilic cytoplasm
  
  • contain fine or coarse azurophilic granules
• lymphocytes look monotonous without reactive features
• IMP:
  
  • morphology is often subtle on aspirate smears as compared to peripheral blood

Question 9

What are the microscopic findings

on the bone marrow biopsy for CLPD-NK cells?

Answer 9

• the infiltrates are subtle in the bone marrow
  
  • intrasinusoidal and interstitial infiltrates
• cells are small with irregular nuclear contours
• modest amounts of pale cytoplasm
• need IHC to identify

Question 10

What is the immunophenotype

of CLPD-NK cells ?

Answer 10

• unique immunophenotype
  
  • sCD3 is negative
  • cCD3 (epsilon) is positive
  • CD16 is positive
  • CD56 weak expression
  • cytotoxic markers are positive
    
    • TIA1, Granzyme B and Granzyme M
• abnormal diminished or loss of:
  
  • CD2, CD7, CD57
• abnormal uniform expression of CD8

Question 11

What are the unique immunophenotypic

findings of CLPD-NK cells ?

Answer 11

• Killer-cell immunoglobulin like cell receptors (KIRS)
  
  • Cd158a, Cd158b, CD158e
  • either restricted isoform seen or lack of expression
• Other markers:
  
  • CD94 (NKG2A)- uniform bright expression
  • CD161 - positive

Question 12

What is the genetic profile

of CLPD-NK ?

Answer 12

• karyotype is usually normal in most cases
• activation of STAT3 SH2
  
  • 1/3 of cases
  • presence of this excludes the possibility of a reactive process
• IMP:
  
  • No IG and TR gene rearrangements
  • this is expected in NK cells

Question 13

What are the prognostic and predictive

factors in CLPD-NK ?

Answer 13

• indolent clinical course for many years
• no therapy is needed
• possible indicators of worse prognosis:
  
  • cytopenias
  • recurrent infections
  • comorbidity
  • cytogenetic abnormalities - may indicate a propensity to transformation (rare occurrence)

Question 14

What is the definition of

aggressive NK cell leukemia ?

Answer 14

• neoplastic proliferation of NK cells
• often associated with EBV infection
• aggressive clinical course

Question 15

What is the epidemiology and etiology

of ANK-leukemia ?

Answer 15

• rare form of leukemia
• typically common in Asians
  
  • median 40s
  • peak in third and fifth decades
• associated with EBV infection
  
  • in younger patients may represent evolution from chronic active EBV

Question 16

What is the localization of

ANK-leukemia ?

Answer 16

• peripheral blood, BM
• liver and spleen
• note:
  
  • any organ can be infiltrated

Question 17

What is an important diagnostic

differential for ANK-leukemia ?

Answer 17

• Extranodal NK/T cell lymphoma
  
  • that has disseminated to different organs
• IMP
  
  • unclear whether ANK-leukemia just represents the leukemic counterpart of this disease.

Question 18

What are the clinical features of

ANK-leukemia ?

Answer 18

• fever and constitutional symptoms (leukemic blood picture)
• number of circulating leukemic cells may be low or high
• cytopenias (common)
  
  • anemia, neutropenia and thrombocytopenia
• hepatosplenomegaly and lymphoadenopathy can be seen
  
  • skin lesions are uncommon
• effusions are common
• coagulopathy, HLH and multiorgan failure

Question 19

What are the microscopic features

ANK-leukemia ?

Answer 19

• variable morphology
  
  • PB: normal LGL to cells with atypical nuclei
    
    • cytoplasm is moderate with azurophilic granules
  • BM
    
    • massive, focal or subtle infiltrates
    • intermingled reactive histiocytes with hemophagocytosis
    • infiltrates appear monotonous with round, irregular nuclei, condensed chromatin, and small nucleoli (substantial nuclear pleomorphism can be seen sometimes)
    • necrosis is common
      
      • may not have angioinvasion

Question 20

What is the immunophenotype of the cells

in ANK-leukemia ?

Answer 20

• negative
  
  • sCD3, CD5
  • CD57 (usually)
• positive:
  
  • CD2, cCD3 epsilon, CD56
  • cytotoxic molecules
  • CD16, CD11b (somtimes expressed)
• IMP
  
  • this immunophenotype is identical to extranodal NK/T cell lymphoma except that the CD16 is positive in >75% of cases
• variable aberrant immunophenotypes
  
  • loss of CD2, CD7, CD45

Question 21

What protein is expressed highly by

ANK-leukemia cells that can be detected in serum ?

Answer 21

• FASL

Question 22

What is the genetic profile

of ANK-leukemia?

Answer 22

• TR genes are in germline configuration
• EBV is positive in 85-100% of cases
  
  • present in a clonal episomal form
• some cytogenetic abnormalities have been reported
  
  • del6q
  • 11q deletion
  • these are different from those seen in Extranodal NK/T cell lymphoma

Question 23

What are the prognostic and predictive

factors for ANK-leukemia ?

Answer 23

• fulminant clinical course
• multiorgan failure, coagulopathy and HLH
• median survival < 2 months
• poor response to chemotherapy with frequent relapses even with BMT