T-lymphoblastic leukemia/lymphoma

Question 1

What is the definition of T-ALL/LBL ?

Answer 1

• lymphoblasts are committed to the T cell lineage
  
  • small to medium sized blasts with scant cytoplasm
  • moderately condense chromatin
  • inconspicuous nucleoli
  • involve bone marrow and blood
  • OR primary thymus or nodal and/or extranodal involvement
• most protocols use >25% bone marrow blasts to define leukemia
  
  • no agreed upon lower limit to diagnose ALL
  • but diagnosis should be avoided with < 20% blasts

Question 2

What is the etiology and epidemiology

of T-ALL ?

Answer 2

• accounts for 15% of all childhood ALL cases
• more common in adolescents than kids
• more common in males
• accounts for 25% of adult ALL cases **
  
  • T-LBL represents 80-90% of those cases

Question 3

What is the localization of

T-ALL ?

Answer 3

• bone marrow is involved in all cases
• aleukemic presentations in the setting of bone marrow replacement are uncommon
  
  • unlike in B-ALL
• T-LBL
  
  • frequently involves the thymus /mediustinum
  • can involve any lymph node or extranodal site
    
    • skin, tonsils, liver, spleen, CNS and testes

Question 4

What are the clinical features of

T-ALL ?

Answer 4

• usually presents with a high leukocyte count and with tissue mass and or large mediastinal mass (with rapid growth)
• lymphadenopathy and hepatosplenomegaly are common
• IMP
  
  • unlike B-ALL…T-ALL often spares bone marrow hematopoiesis
• pleural effusions and respiratory compromise are common

Question 5

What are the microscopic findings in

lymph nodes/extranodal tissue?

Answer 5

• morphologically indistinguishable from B-ALL
• cells are medium in size with high N:C ratio
  
  • but there can be significant range in size
• nuclei can be round to very irregular and vacuoles can be seen
• IMP:
  
  • sometimes blasts can resemble mature T lymphocytes so IHC is needed to differentiate from mature peripheral T cell NOS

Question 6

What are the microscopic findings

in the bone marrow sections ?

Answer 6

• high NC ratio, thin nuclear membrane, fine, stippled chromatin and inconspicuous nucleoli
• mitotic figures are higher in T-ALL vs. B-ALL
• In LN
  
  • complete effacement with involvement of the capsule
  • partial involvement with paracortical location and sparing of the GC can be seen
    
    • it can sometimes mimic follicular lymphoma
    • starry sky can mimic Burkitt but the cytoplasm and nucleoli are less prominent in T-LBL
  • mitotic figures are numerous

Question 7

What is the genetic abnormality in T-ALL

associated with a significant eosinophilic infiltrate?

Answer 7

• association can be seen with 8p11.2 cytogenetic abnormality involving the FGFR1 gene

Question 8

What is the immunophenotype of

T-ALL ?

Answer 8

• usually TdT positive
• variable expression of:
  
  • CD1a, CD2, CD3, CD4, CD5, CD7 and CD8
  • cCD3 and CD7 are the most common positive markers
    
    • but only CD3 is considered lineage specific
  • CD4 and CD8 are often co-expressed in the blasts
• In addition to TdT and CD34
  
  • CD1a and CD99 may help indicate the precursor nature of the T lymphoblasts

Question 9

Rarely, T-ALL can show expression of CD117. What do

those cases correlate with ?

Answer 9

• CD117 is only occasionally positive in cases
• associated with FLT3 activating mutations

IMP: the presence of myeloid markers does not exclude a T-ALL

Question 10

Can T-ALL express CD56?

Answer 10

• CD56 expression, is very characteristic of NK cells
  
  • BUT this does not exclude a T cell leukemia
• BUT there is an entity called an NK cell ALL/LBL
  
  • very difficult to differentiate from T-ALL
  • often expresses shared markers CD2, CD7 and even sometimes CD5

Question 11

What is the genetic profile of antigen receptors

in T-ALL ?

Answer 11

• almost always shows clonal rearrangements of the T cell receptor (TR) genes
• simultaneous presence of IGH gene rearrangements

Question 12

What other genetic findings are present

in T-ALL ?

Answer 12

• 50-70% have an abnormal karyotype
• most commonly involved genes are TLX1(HOX11) and TLX3 (HOX11L2)
  
  • these are transcription factors
  • TLX1 on 10q24.3
    
    • involved in 7% of childhood and 30% of adult cases
  • TLX3 on 5q35.1
    
    • involved in 20% of childhood and 10-15% of adult cases

IMP: any translocations of genes are usually missed by karyotype and only are seen by molecular genetic studies.

Question 13

What are other important translocations in

T-ALL ?

Answer 13

• t(10;11)(p1.3;q14.2)
  
  • PICALM-MLLT10
  • found in 10% of cases
• KMT2A translocations
  
  • occur in 8% of cases
  • frequently lead to activation of HOXA genes

Proposal to subgroup the T-ALLs by genetics and degree of maturation arrest.

Question 14

What genetic group in T-ALL seems to have a

favorable prognosis ?

Answer 14

• The TLX1 group seems to have a relatively favorable prognosis

Question 15

What is the most common deletion that

occurs in T-ALL ?

Answer 15

• del(9p)
• results in a loss of tumor suppressor gene CDKN2A
  
  • this is an inhibitor of the cyclin-dependent kinase CDK4
• this occurs in ~30% of cases by cytogenetics and more frequently by molecular testing
• this leads to a loss of G1 control over the cell cycle

Question 16

What is another frequent molecular mutation

identified in T-ALL ?

Answer 16

• ~50% of cases have activating mutations involving the PEST domain of NOTCH1
• this encodes a protein critical for early T cell development
• the direct downstream target of NOTCH1 appears to be MYC
  
  • this contributes to the growth of neoplastic cells
• IMP: NOTCH1 mutation is associated with shorter survival in adults but not pediatric patients
• 30% of cases have mutations in FBXW7
  
  • this is a negative regulator of NOTCH
  • results in an increased half life of NOTCH1 protein

Question 17

What are the prognosis and predictive factors of T-ALL ?

Answer 17

• in childhood, T-ALL is considered higher risk compared to B-ALL
  
  • usually in part to higher risk features such as older age and higher WBC count
• Compared to B-ALL, T-ALL
  
  • associated with a higher risk of induction failure
  • early relapse
  • isolated CNS relapse
• WBC is not a strong risk factor
• MRD following therapy is a strong adverse prognostic factor
• IMP: prognosis of T-ALL in adults may be better than that of B-ALL

Question 18

What is the definition of early T cell precursors

lymphoblastic leukemia (ETP-ALL) ?

Answer 18

• neoplasm showing only limited, early T cell differentiation

Question 19

What is the epidemiology of ETP-ALL ?

Answer 19

• uncommon neoplasm found in children and adults
• accounts for ~10-13% of cases of T-ALL in childhood
  
  • 5-10% of cases of T-ALL in adulthood

Microscopically the blasts look similar to other T-ALL

Question 20

What is the immunophenotype of ETP-ALL ?

Answer 20

• expresses CD7 but by definition lacks CD8 and CD1a
• positive for one or more myeloid markers
• blasts are also positive for cCD3
• may express CD2 and or CD4
• CD5 is often negative
  
  • IF positive it must be less than 75% of the cells
• IMP
  
  • MPO must be negative because otherwise it would be classified as an MPAL

Question 21

What is the cell of origin for

ETP-ALL ?

Answer 21

• derived from a subset of cells that have immigrated to the thymus from the bone marrow
• cells are not yet irreversibly commited to the T cell lineage
  
  • have potential for myeloid and dendritic cell differentiation

Question 22

What is the genetic profile of ETP-ALL ?

Answer 22

• gene expression profile is similar to that of normal early thymocyte precursors and different from that of cases of T-ALL
• they have many genes that are typically associated with myeloid stem cell profiles
  
  • CD44, CD34
  • KIT, GATA2
  • CEBPA

Question 23

Whate genes are frequently mutated

in ETP-ALL ?

Answer 23

• high frequencies of genes seen in myeloid leukemias
  
  • FLT3
  • the RAS family of genes
  • DNMT3A
  • IDH1 and IDH2
• mutations that are typically seen in ALL are in much less frequency
  
  • NOTCH1
  • CDKN1/2 genes

Question 24

What are the prognostic and predictive

factors in ETP-ALL ?

Answer 24

• with modern therapies overall outcome of ETP-ALL vs. T-ALL are similar
• ETP-ALL is more likely to have MRD at the end of induction
• too few studies in adults to say definitively