T-cell large granular lymphocytic leukaemia (T-LGL)

Epidemiology and Etiology:

• Heterogeneous
• Persistent (> 6 months) increase in peripheral blood large granular lymphocytes (LGL)
• Clonal T-LGL cells retain many phenotypic and functional properties of normal cytotoxic effector T-cells
• Without a clearly identified cause
• Frequent association with autoimmune disorders
• Rheumatoid arthritis
• Post-allogeneic BM transplant
• Post-transplant lymphoproliferative disorder rarely
• In association with low grade B-cell malignancies
• Hairy cell leukaemia
• Chronic lymphocytic leukaemia
• Usually stable, do not progress to clinically significant disease
• CD4+ subset is frequently (30%) associated with malignancy

Common sites:

• PB
• BM
• Liver
• Spleen
• Rare for lymphadenopathy

Gross features:

• Moderate splenomegaly

Histologic features:

Immunophenotype:

Marker:	Sensitivity:	Specificity:
CD2
CD3
CD8
CD57
Alpha beta TCR
CD4	Uncommon variant
Gamma delta TCR	Uncommon variant; CD8+ or CD4/CD8-negative
CD5 (dim or neg)	Common
CD7 (dim or neg)	Common
CD57	>80%
CD16	> 80%
CD94 / NKG2 family and KIR family members MHC class I receptors	>= 50%
CD56	Infrequent
TIA1
Granzyme B
Granzyme M

• (Mature cytotoxic T-cells immunophenotype, or variant with NK-cell immunophenotype

Molecular features:

• Clonal TCR rearrangement (as a rule)
• TRG@ gene rearranged in all cases regardless of type of receptors expressed
• TRB@ gene usually rearranged, but may be in germline configuration in cases expressing the TCR gamma-delta
• Deep sequencing of the TRB CDR3 has demonstrated that the dominant clonotypes in the CD8+ LGLs tend to be private and not commonly shared in the CDR3 repertoire seen in normal individuals
• STAT3 mutation (~1/3)
• Activating somatic mutations affecting the SH2 domain
• Heterozygous (vast majority)
• Codon Y640 or D661 (most frequently)
• Possible association with more symptomatic disease and shorter time to treatment failure, but no OS impact
• Rarely STAT5B SH2 domain mutations
• N642H mutation may be associated with more aggressive disease
• No unique karyotypic abnormality
• Numeric and structural abnormalities have been described in a small number of cases

Other features:

• Large granular lymphocytes 2-20x10⁹/L
• Indolent course most cases (?should be regarded as a clonal disorder of uncertain significance?)
• Non-progressive typically
• Mortality uncommon
• Median survival 13 y.
• Rare cases with an aggressive course (may be peripheralization of a peripheral T-cell lymphoma)
• Rare cases spontaneously regress
• Morbidity associated with cytopenias esp. neutropenia
• Severe neutropenia +/- anemia is frequent
• Autoantibodies in serum
• Immune complexes in serum
• hypergammaglobulinemia

References: