Peripheral T-cell lymphomas (leukaemic and extranodal)

Alma Mater Studiorum 1088 d.C.

T-cell prolymphocytic leukemia 2% of cases of mature lymphocytic leukaemia Clinical features Median age (range) M : F ratio Hepatosplenomegaly Lymphadenopathy Skin lesions Effusions WBC x 109/L Hb < 10 g/dl Platelets < 100 x 109/L

65 years (30 - 94) 1. 3 79% 46% 23% 12% > 100 25% 44%

Morphology: Prolymphocytic 75%

Cytoplasmic protrusions or blebs Peripheral blood

Small cell 20%

Lymph node

Cerebriform 5%

Peripheral blood

T-PLL hairy cell leukaemia-like

CD3

Immunophenotype Antigen

% of cases+

CD3

84

CD4+/CD8-

60

CD4+/CD8+

25

CD4-/CD8+

10

TCL1

71

CD3+ BM infiltrate

All: CD52+, CD2+, CD5+, CD7+, TdT-, CD1a-, NK markers-. Cytotoxic markes: negative.

Complex karyotype

ATM

p53 del

TCL1 70-80%

80%

Prognosis and predictive factors • Median survival less than 1 year • Cases with a more chronic course: accelerated phase after 2-3 years • Alemtuzumab • Autologous or allogeneic stem cell transplantation • High expression of TCL-1 and AKT: poor outcome

T-cell LGL leukaemia

(2-3% of mature lymphocytic leukaemias) Definition: increased number of circulating LGLs (2-20x109/L) lasting at least 6 months and without a clearly identified cause, often arising in a setting of immune stimulation Clinical features: -

No clear-cut sex and age prevalence (45-75 years)

-

involvement of the peripheral blood, bone marrow, liver and spleen

-

severe neutropenia with/without anaemia

-

possible recurrent bacterial infections

-

moderate splenomegaly

-

frequent association with rheumatoid arthritis, auto-antibodies

-

circulating immune complexes and hypergammaglobulinemia

-

T-LGL clonal expansions following allogeneic BMT

-

typically indolent clinical course

Azurophilic granules e.m.: parallel tubular arrays; cytotoxic proteins.

50%: hypercellular 50%: normo/hypocellular

Mild fibrosis

Dis-maturation of the haematopoietic series!

Spleen

BM biopsy misleading without IHC

Phenotype: TIA-1+, Granzyme B+, Granzyme M+, perforin+, CD57+v High expression of FAS and FAS-L CD3+,

TCRα/β+,

CD4-,

CD8+

80%: variants: CD3+, TCRα/β+, CD4+, CD8CD3+, TCRα/β+, CD4+, CD8+ CD3+, TCRγ/δ+, CD4v, CD8v CD5 and CD7 expression: weak or absent

Genotype: TCR γ (+β) clonal rearrangement

CD3

CD57

Reactive nodules with mixed composition (3+, 4+>8+, CD20+)

CD4

CD4

CD20

CD8

Chronic NK-cell LPD • Morphologically LGL (blood and BM involvement) • Phenotypically abnormal NK-cells (CD3e+, CD16+, CD56+w, cytotoxic markers+, CD2-, CD7-, CD57-, CD5+, CD8+, EBV-) • Blood LGL count ≥ 2x109/L • Without obvious cause for the elevation • Persists for > 6 months • Associated with solid and haematological tumours, vasculitis, splenectomy, neuropathy and autoimmune disorders • No worsening of the lympho-proliferation or clinical condition • Exceptional transformation to an aggressive NK-cell disorder

Granzyme B

Phenotype & genotype CD2+ CD3CD3e+ CD56+ CD16+/CD57 usuallycytotoxic molecules+ (TIA-1; GB; perforin) TCR genes: germ line configuration EBV-

Neither TCR rearrangement nor karyotype abnormalities, but hints of clonality! •

X-chromosome inactivation – HUMARA

•

Immunophenotyping – Unique profile of markers – Restricted KIR expression pattern

KIR (killer cell Ig-like receptors) • Located on 19p13.4 • Polymorphic in the KIR genes present and in the allele represented • May have 2 or 3 Ig-like domain (2D,3D). • May have a long or short cytoplasmic tail (L or S forms) • Long forms can transduce signals but short forms need to associate with adaptors for signal transduction eg. DAP12 • Can be activating or inhibitory but normal NK cells always have one or more inhibitory

KIRs

Aggressive NK-cell leukaemia (EBV+) Clinical features

rare (higher prevalence among Asians) young to middle-aged adults (mean age: 42 yrs) no sex predilection at onset: leukaemic blood picture, fever, Bsymptoms hepatosplenomegaly: common lymphadenopathy: occasional skin lesions: uncommon elevated serum soluble FAS-L levels

Complications

coagulopathy haemophagocytic syndrome multi-organ failure

Clinical course

more often fulminant (mean survival: 2 months)

Marrow

Spleen

Testis

Phenotype & genotype CD2+ CD3CD3e+ CD56+ CD16+/CD57 usuallycytotoxic molecules+ (TIA-1; GB; perforin) TCR genes: germ line configuration del(6)(q21;q25) EBV+

CD3ε

CD56

Adult T-cell lymphoma/leukaemia - Discovered by Takatsuki et al. (1976) - Endemic in: Southern Japan, Caribbean basin, and Central Africa - The disease is linked to the prevalence of HTLV-1 in the population - Incidence: 2.5% among HTLV-1 carriers - Exposure to the virus in the early life (breast milk, blood and blood products) - Long latency - Adults (20 - 80 yrs-old) with M/F = 1.5/1 - HTLV-1 not sufficient to result in neoplastic transformation

Adult T-cell lymphoma/leukaemia Clinical variants: acute: leukaemic phase, lymphadenopathy, hepatosplenomegaly, skin rash, hypercalcaemia (lytic bone lesions) and associated Tcell immunodeficiency lymphomatous: prominent lymphadenopathy without PB involvement, cutaneous lesions common, hypercalcaemia less often seen chronic: exfoliative skin rush, mild leukaemic component, hypercalcaemia absent smouldering: >5% circulating neoplastic cells, frequent skin or pulmonary lesions Progression to an acute variant in 25% of chronic or smouldering cases

Overall survival of ATLL according to clinical subtypes

Shimoyama et al Brit J Haematol 1991

Nagasaki Unv. Leuk Res 1993

Diversity of leukaemic cell morphology in ATLL x1000

Acute

x1000

Smoldering

Acute crisis

x1000 x1000

Acute Chronic

x1000 Acute

x400 Cytomorphological Type (% lymph)

Acute (n=36)

Chronic (n=14)

p Value

Prototype CLL-like Unusual Intermediate

49% 17% 20% 8%

29% 52% 3% 10%

0.015