T-cell Prolymphocytic Leukemia

Question 1

What is the definition of

T-PLL ?

Answer 1

• aggressive T-cell leukemia
• characterized by small to medium prolymphocytes
• mature, post thymic T-cell phenotype
• involves:
  
  • bone marrow
  • lymph nodes
  • liver
  • spleen
  • skin

Question 2

What is the epidemiology and localization ?

Answer 2

• T-PLL is rare, only about 2% of mature lymphocytic leukemias in adults >30 years of age
• median patient age is 65
• very infrequent among individuals aged less than 30 years
• leukemic cells can be found
  
  • bone marrow
  • peripheral blood
  • lymph nodes
  • spleen , liver
  • skin (sometimes)

Question 3

What is the clinical presentation

of T-PLL ?

Answer 3

• hepatosplenomegaly (common) with generalized lymphadenopathy
• skin infiltration 20%
• serous effusions in a minority
• anemia and thrombocytopenia are common
• lymphocyte count is usually high
  
  • >100 x 10^9/L
• serum immunoglobulins are normal
• serology for HTLV1 is negative

Question 4

What are the microscopic findings of

the peripheral blood and bone marrow ?

Answer 4

• usually diagnosis is made on peripheral blood films
• demonstrates predominance of small to medium-sized lymphoid cells
• non-granular, basophilic cytoplasm
• round-oval or markedly irregular nuclei
  
  • visible nucleoli
• cytoplasmic blebs are common finding
• Note:
  
  • 25% of cases are small and nucleolus may not be visible
    
    • small cell variant
  • 5% of cases have very irregular cerebriform nuclei
    
    • cerebriform variant
• bone marrow is usually diffusely infiltrated

Question 5

What is the pattern of

involvement of the skin ?

Answer 5

• perivascular and periadnexal
• sometimes more diffuse dermal infiltrate without epidermotropism

Question 6

What is the pattern of involvement of the spleen ?

Answer 6

• dense red pulp infiltrate
• invades the spleen capsule, blood vessels
• leads to atrophic white pulp

Question 7

What is the pattern of involvement of

the lymph nodes ?

Answer 7

• involvement is diffuse
• tends to predominate in the paracortical areas
  
  • sometimes spares the follicles

Note: prominent high endothelial venules may be numerous and are often infiltrated by neoplastic cells

Question 8

What cytochemistry is seen

in T-PLL ?

Answer 8

• positive, strongly for alpha-naphthyl acetate esterase and acid phosphatase
  
  • usually a dot like pattern

Note: cytochemistry is rarely used for diagnosis

Question 9

What is the immunophenotype of

T-PLL ?

Answer 9

• negative:
  
  • TdT and CD1a
• positive:
  
  • CD2, CD3, CD5 and CD7 (usually bright)
  • CD3 may be weak
  • CD52 is usually expressed in high density and can be used as targeted therapy
  • CD4 > CD8 (60% of cases)
    
    • IMP: CD4 and CD8 double positive in 25%
      
      • this is characteristic of T-PLL (almost exclusive)

Question 10

What marker is characteristically seen in T-PLL

and is helpful in evaluating residual disease ?

Answer 10

• TCL1
• IHC and Flow cytometry

Question 11

Which IHC marker has been seen in

30% of cases and can be a pitfall ?

Answer 11

• S100

Question 12

What is the normal counterpart of T-PLL ?

Answer 12

• unknown T cell with mature (post-thymic immunophenotype)
• the strong CD7 expression along with
  
  • weak CD3
  • coexpression of CD4 and CD8 in 25% of cases
  • suggests its a T cell at the intermediate stage of differentiation between a cortical thymocyte and mature T lymphocyte

Question 13

Are the T-cell genes rearranged ?

Answer 13

• TRB and TRG are clonally rearranged

Question 14

What are the cytogenetic abnormalities

and oncogenes ?

Answer 14

• IMP:
  
  • Inversion 14 inv(14)
  • breakpoints in long arm q11.2 and q32.1
  • seen in 80% of patients
• 10% of patients show t(14;14)(q11.2;q32.1)
• these translocations juxtapose the TRA locus with oncogenes TCL1A and TCL1B
• less common
  
  • t(X;14)(q28;q11.2)
  • TRA locus with MTCP1 gene

Question 15

How does TCL1 function ?

Answer 15

• inhibits activation induced death in the neoplastic cells

Note: MTCP1 is homologous to TCL1A/B and is oncogenic

IMP: rearrangements of these genes are likely initiating evens but themselves are not oncogenic

Question 16

What are characteristic findings on the

karyotype/cytogenetics for T-PLL ?

Answer 16

• abnormalities of chromosome 8
  
  • idic(8)(p11)
  • t(8;8)(p11-12;q12)
  • trisomy 8q
  • seen in 70-80% of cases
• gains in MYC gene reported by FISH
• deletions of
  
  • 12p13 and 22q
• amplification of
  
  • 5p

Question 17

What other disease is T-PLL assocaited with ?

Answer 17

• Ataxia-telangiectasia
• deletions of 11q22.3 by molecular or FISH studies
  
  • locus for ATM
  • also can see missense mutations

Note: TP53 gene deletion or overexpression is seen in some cases

Question 18

What gene alterations have been identified

by whole exome sequencing ?

Answer 18

• recurrent alterations in the JAK/STAT pathway
  
  • JAK3
  • JAK1
  • STAT5b
  • these mutations are largely exclusive and lead to constitutive activation of the STAT pathway
• rarely genes encoding epigenetic modifiers can be altered
  
  • EZH2 and BCOR
  • described to be recurrently mutated

Question 19

What are the prognostic and predictive factors

for T-PLL ?

Answer 19

• aggressive course with death 1-2 years post diagnosis
  
  • cases with more chronic course have been described but usually progress after 2-3 years
• best response seen with:
  
  • anti-CD52 Alemtuzumab
• autologous or allogeneic transplant should be considered

Question 20

High levels and expression of what markers

have been shown to be worse prognosis

in T-PLL ?

Answer 20

• TCL1
• ATK1

Note: STAT5B mutations have been documented to have negative prognostic impact.