Diagnosis and classification of acute leukaemia

— The acute leukemias are a heterogeneous group of

neoplasms arising from transformation of uncommitted or partially committed hematopoietic stem cells

DIAGNOSTIC EVALUATION

Morphology
— chromatin (fine in myeloblasts, often clumped in

lymphoblasts), — nucleoli (distinct in myeloblasts, variable in lymphoblasts), — cytoplasm (moderate or abundant, often with granules in myeloblasts; scant to moderate, granules uncommon in lymphoblasts) — The granules of standard APL are large and reddish violet; in the microgranular variant of APL, they are indistinct

— Auer rods, — The appearance of more differentiated myeloid

cells in the marrow may provide a clue to myeloid lineage — Erythroid and maturing myeloid precursors may be megaloblastoid in AML, but normal in ALL.

Cytochemistry

— myeloperoxidase (MPO) — Sudan black B (SBB) — nonspecific esterase (NSE)

Immunophenotyping

Panel of monoclonal antibodies to differentiate AML & ALL
— Myeloid Anti-MPO; CD13; CD33; CDw65; CD117 — B lymphoid CD19; cytoplasmic CD22; CD79a;

CD10 — T lymphoid Cytoplasmic CD3; CD2; CD7

Immunophenotypic patterns in AML subtypes
— Undifferentiated

— — — —

(M0) Anti-MPO; CD13; CD33; CD34; CDw65; CD117; negative cytochemistry; lymphoid markers Myelomonocytic (M1-M5): anti-MPO; CD13; CD33; CDw65; CD117 Monocytic (M4 & M5) Stronger expression of CD11b & CD14 Erythroid (M6) Anti-glycophorin A Megakaryocytic (M7) CD41; CD61

Cytogenetic analysis

— patients with AML can be assigned to three broad

prognostic groups and their treatment can be modified accordingly; — specific categories of AML requiring very specific therapeutic strategies can be identified (particularly M3 and M3 variant); — it facilitates the recognition of therapy-related acute leukaemia and the distinction between alkylating agent-related and topoisomerase IIinteractive drug-related leukaemia.

‘Favourable risk’ cytogenetics
— t(8;21)(q22;q22): FAB M2; 5–8% adults <55

years — inv(16)(p13;q22) or t(16;16)(p13;q22): FAB M4Eo; 10% adults <45 years — t(15;17)(q21;q11): FAB M3; 15% adults <45 years

‘Intermediate risk’ cytogenetics
— Normal karyotype: any FAB type; 15–20% adults. — + 8: any FAB type; 10% adults. — abnormal 11q23: >50% infant AML cases; 5–7%

adults; fusion gene MLL. — Others: del(9q); del(7q); +6; +21; +22; –Y and 3– 5 complex abnormalities plus other structural or numerical defects not included in the good risk or poor risk groups

Poor risk’ cytogenetics
— –5/del(5q): any FAB type; >10% adults >45years. — –7/del(7q): any FAB type; >10% adults >45

years. — Complex karyotypes (>5 abnormalities) — Others: t(6;9)(p23;q34); t(3;3)(q21;q96); 20q; 21q; t(9;22); abn 17p.

Molecular genetic analysis

— PML–RARA fusion in AML — Use of all-trans-retinoic acid and possibly arsenic

— — — — — —

trioxide; good prognosis so overtreatment should be avoided AML1–ETO fusion in AML Good prognosis, overtreatment should be avoided High hyperdiploidy in ALL Good prognosis, overtreatment should be avoided BCR–ABL fusion in AML, ALL Poor prognosis in AML and ALL, intensive treatment may be justified and

FRENCH/AMERICAN/BRITIS H DESCRIPTIONS

Acute Leukemia
— L1 — L2 — L3

Lymphoblastic

Acute Myeloid Leukemia
— M0 AML with minimal differentiation — M1 AML without maturation — M2 AML with maturation — M3 Acute promyelocytic leukaemia — M4 Acute myelomonocytic leukaemia — M5a M5b Acute monoblastic/monocytic leukaemia — M6 Acute erythroleukaemia — M7 Acute megakaryoblastic leukaemia

W HO CLASSIFICATION

WHO criteria for the diagnosis of acute myeloid leukaemia
— Blast cells are 20% or more in either peripheral

blood or bone marrow — Presence of Ø t(8;21)(q22;q22) or AML1–ETO fusion gene Ø inv(16)(p13q22) or t(16;16)(p13;q22) or CBFB– MYH11 fusion gene Ø t(15;17)(q22;q12) and variants or PML–RARA fusion gene or variants Ø Translocation with an 11q23 breakpoint and MLL gene rearrangement

The AML classification includes four groups:

ACUTE MYELOID RECURRENT ABNORMALITIES
— recurring — — — —

LEUKEMIA WITH CYTOGENETIC
translocations and

balanced

inversions;; lack multilineage background dysplasia; tend to respond favorably to cytotoxic chemotherapy; unrelated pathogenetically to MDS They comprise approximately 85% of AML in young patients but only a small percent of cases in the elderly.

ACUTE MYELOID LEUKEMIA WITH MULTILINEAGE DYSPLASIA
— cytogenetic abnormalities shared with MDS; — an

— — — —

exponentially increasing incidence with advancing age (similar to MDS), with median age in the 70s; tend to have multilineage background dysplasia; clonal background and remission hematopoiesis; respond poorly to cytotoxic chemotherapy, related pathogenetically to MDS

ACUTE MYELOID LEUKEMIA, THERAPY RELATED
— Alkylating agent–related AML.Peak incidence is

approximately 5 years after exposure. It is often preceded by MDS. — Topoisomerase II inhibitor–related AML.

ACUTE MYELOID LEUKEMIA NOT OTHERWISE CATEGORIZED
— Acute basophilic leukemia — Acute panmyelosis with myelofibrosis — Myeloid sarcoma

Acute Leukemia

Lymphoblastic

— PRECURSOR B-LYMPHOBLASTIC — PRECURSOR T-LYMPHOBLASTIC — BURKITT LYMPHOMA/LEUKEMIA

Acute Leukemia of Ambiguous Lineage
— cases with apparent differentiation to more than

one lineage, usually T/myeloid or B/myeloid (biphenotypic acute leukemia), — cases with no discernible further differentiation beyond hematopoietic stem cells using current techniques (undifferentiated acute leukemia) .

Conclusion
— The diagnosis and further classification of acute

leukaemia requires: 1. a full assessment of the medical history, family history and physical findings, 2. assessment of cytological features in blood and bone marrow 3. cytochemistry is selective 4. Application of immunophenotyping can be selective but is tending to become universal 5. cytogenetic analysis should be universally applied, with molecular analysis being used selectively.