T-lymphoblastic leukemia/lymphoma Flashcards
What is the definition of T-ALL/LBL ?
- 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
What is the etiology and epidemiology
of T-ALL ?
- 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
What is the localization of
T-ALL ?
- 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
What are the clinical features of
T-ALL ?
- 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
What are the microscopic findings in
lymph nodes/extranodal tissue?
- 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
What are the microscopic findings
in the bone marrow sections ?
- 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
What is the genetic abnormality in T-ALL
associated with a significant eosinophilic infiltrate?
- association can be seen with 8p11.2 cytogenetic abnormality involving the FGFR1 gene
What is the immunophenotype of
T-ALL ?
- 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
Rarely, T-ALL can show expression of CD117. What do
those cases correlate with ?
- CD117 is only occasionally positive in cases
- associated with FLT3 activating mutations
IMP: the presence of myeloid markers does not exclude a T-ALL
Can T-ALL express CD56?
- 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
What is the genetic profile of antigen receptors
in T-ALL ?
- almost always shows clonal rearrangements of the T cell receptor (TR) genes
- simultaneous presence of IGH gene rearrangements
What other genetic findings are present
in T-ALL ?
- 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.
What are other important translocations in
T-ALL ?
- 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.
What genetic group in T-ALL seems to have a
favorable prognosis ?
- The TLX1 group seems to have a relatively favorable prognosis
What is the most common deletion that
occurs in T-ALL ?
- 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
What is another frequent molecular mutation
identified in T-ALL ?
- ~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
What are the prognosis and predictive factors of T-ALL ?
- 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
What is the definition of early T cell precursors
lymphoblastic leukemia (ETP-ALL) ?
- neoplasm showing only limited, early T cell differentiation
What is the epidemiology of ETP-ALL ?
- 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
What is the immunophenotype of ETP-ALL ?
- 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
What is the cell of origin for
ETP-ALL ?
- 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
What is the genetic profile of ETP-ALL ?
- 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
Whate genes are frequently mutated
in ETP-ALL ?
- 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
What are the prognostic and predictive
factors in ETP-ALL ?
- 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
