T-lymphoblastic leukemia / lymphoma (T-ALL) (T-LBL)

Epidemiology and Etiology:

• Late childhood, adolescence, and young adulthood (most commonly)
• 15% of childhood ALL
• 25% of adult ALL
• T-LBL accounts for 25-30% of childhood non-Hodgkin lymphomas
• M > F
• Increased risk for ataxia telangiectasia patients (ATM)

Common sites:

• Mediastinum
• Thymus
• Lymph nodes (supradiaphragmatic often)
• Pleural fluid often
• Bone marrow (majority during course)
• Peripheral blood (majority during course)
• CNS involvement is common

Gross features:

•  Presents more like a lymphoma with mass(es)

Cytologic / Histologic features:

•  Cytology:
• Lymphoblasts
• Small to medium / larger cells
• Small cells:
• scant cytoplasm
• condensed nuclear chromatin
• indistinct nucleoli
• larger cells:
• moderate amount of cytoplasm
• dispersed chromatin
• multiple nucleoli
• azurophilic granules maybe
• Thymus:
• normal thymus structure effaced (important differentiating feature from B-type thymomas)
• epithelial meshwork destroyed
• septa effaced
• tumour cells spread through the capsule into adjacent mediastinal tissue (into mediastinal fat)
• starry sky pattern maybe
• less prominent than Burkitt
• lymphoblasts
• small to medium sized
• scant cytoplasm
• round, oval, or convoluted nuclei with fine chromatin and indistinct or small nucleoli
• larger cells with prominent nucleoli maybe
• mitotic figures numerous
• Lymph node:
• Infiltrative rather than destructive pattern
• Partial preservation of the subcapsular sinus and germinal centres

o Increased eosinophils in some cases (assocated with FGFR1 gene rearrangement

Immunophenotype:

Marker:	Sensitivity:	Specificity:
TdT	usually	Good
CD34		Good
CD7	variable
CD3	+/-
Other pan T	Variable
CD1a	+/-	Good
CD4 / CD8 (double positive or double negative)	Often variable
Ig (neg)
Pan B (neg)
CD99		Not good
CD2	Variable
CD5	Variable
CD10	Variable
TCR	Variable Alpha/beta (majority) Gamma/delta (minority)
CD79a	12% of LBLs Not enough for mixed phenotype
CD13 and/or CD33	Subset of T-LBLs Not enough for mixed phenotype
CD19, CD22, PAX5, MPO	Enough for mixed phenotype ALL if expressed in CD3+ neoplasm

• Immunophenotype of blasts may be indistinguishable from cortical thymocytes (such as in thymomas)
• Expression ranges from early or pro-T and pre-T (cytoplasmic CD3+, CD1a-, CD4-, CD8-) to cortical thymocyte (CD1a+, surface CD3+, CD4+, and CD8+) to late thymocyte (CD1a-, surface CD3+, CD4 or CD8+)
• Rare cases of T-LBL have immature NK cell phenotype (cytoplasmic CD3+, CD56+)
• Minimal histopathological criteria for classification as T-LBL are expression of CD3 in a TdT-positive lymphoma when B-cell CD19 and myeloid differentiation (MPO or monocytic markers) is not detectable

Molecular features:

• Clonal TCR gene rearrangement (almost all)
• Clonal IgH gene rearrangement (~20%)

§ mutations:

· NOTCH1 activating mutations (50%) (?favourable prognosis)

o Protein critical for early T-cell development

o MYC is direct downstream target

o Associated with shorter survival in adults but not pediatric patients (in one study)

· FBXW7 mutations (30%)

o Negative regulator of NOTCH1

o Result in increased half-life of the Notch1 protein

§ Abnormal karyotype in 50-70%

• 14q11-q14 abnormalities (alpha and delta TCR loci)
• 7q35 abnormalities (beta TCR locus)
• Most cases involve dysregulation of the transcription of the partner gene by juxtaposition with the regulatory region of one of the TCR loci
• HOX11 (TLX1) (10q24) (7% childhood, 30% adult)
• HOX11L2 (TLX3) (5q35) (20% childhood, 10-15% adult)
• MYC (8q24.1)
• TAL1 (1p32) (3%)
• Translocation seen by karyotype in only 3%
• Usually it is fused to the SIL gene by a cryptic interstitial deletion at 1p32
• Aberrant TAL1 expression interferes with differentiation and proliferation by inhibiting the transcriptional activity of E47/HEB
• RBTN1 (LMO1) (11p15)
• RBTN2 (LMO2) (11p13)
• LYL1 (19p13)
• LCK (1p34.3-35)
• Cytoplasmic tyrosine kinase
• TAL1 rearrangements (1p32) (20-30%)
• Usually it is fused to the SIL gene by a cryptic interstitial deletion at 1p32
• Aberrant TAL1 expression interferes with differentiation and proliferation by inhibiting the transcriptional activity of E47/HEB
• PICALM-MLLT10 translocation [CALM-AF10; t(10;11)(p13;q14)] (10%)
• Poor prognosis (dependent on stage of maturation arrest)
• Not specific to T-ALL
• MLL translocations (8%)
• Most often with partner ENL at 19p13
• Not specific to T-ALL
• MLL deletion
• Of a single exon
• FGFR1 rearrangements (8p11) (rare) (poor prognosis):
• t(8;13)(p11;q12) – ZNF198-FGFR1 is most common
• 8 fusion partners reported
• Morphologies:
• T-LBL with accompanying eosinophilia often
• B-LBL
• CEL
• AML
• Poor prognosis
• Not responsive to imatinib
• Deletions:
• del(9p) (loss of CDKN2A) (30% by cytogenetics, higher by molecular)
• leads to loss of G1 control of cell cycle
• may have a poor prognosis
• del(6)(q) (5-13% of ALL, both B and T) (?poor prognosis)
• considerably variable breakpoints
• critical region has not been found; likely multiple genes involved
• GRIK2 (6q16) is a candidate
• most common are 6q15-q21
• terminal deletions are actually interstitial
• characteristic of lymphoid malignancies in general (NHL and CLL)
• usually in association with other abnormalities
• no evidence for impact on prognosis
• 11q deletion (ATM)
• 17p deletion (TP53)
• TCR-gamma gene biallelic deletion (?favourable prognosis)

§ Aberrant expression of TAL1, LYL1, HOX11, and HOX11L2 are mutually exclusive from each other and also from PICALM and MLL translocations

§ In many cases translocations are not detected by karyotyping but only by molecular genetic studies

§ Gene expression profiling:

· HOX11+ group appears to have a relatively favourable prognosis

Other features:

• Poor prognosis overall compared to B-ALL
• Prognosis of individual cytogenetic groups in T-ALL remains unclear (numbers are relatively small)
• Does not appear to correlate with immunophenotype or genetic abnormalities, with aggressive therapy
• Distinction between T-ALL and T-LBL is the presence / absence of peripheral blood and bone marrow involvement
• Presents as symptomatic large mediastinal mass
• Pleural or pericardial effusions often
• Airway compromise common
• Medical emergency often

References:

• Swerdlow. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. WHO Publications; 2008.
• Travis WD et al. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart, 4^th ed. (2015)