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PA18.1-2 | Acute Leukaemias — AML & ALL — Part 2

Classification: WHO 2022 and FAB

A four-panel medical education diagram comparing WHO 2022 genetic-lineage classification of acute leukaemias with FAB morphology and cytochemistry-based AML examples. — **Panel A:** WHO 2022 classification flowchart showing acute leukaemia divided by lineage into AML and ALL, with AML categories and B- versus T-lymphoblastic entities.. **Panel B:** Key defining genetic abnormalities shown with chromosome and gene-fusion tags including t(8;21), t(15;17), BCR::ABL1, ETV6::RUNX1, hyperdiploidy, and hypodiploidy.. **Panel C:** FAB classification principle showing blast morphology, Auer rods, MPO-positive granules, MPO-negative blasts, and cytochemistry staining.. **Panel D:** Compact FAB AML example table illustrating M0, M1, M2, and M3 with key features including MPO status, maturation, Auer rods, t(8;21), t(15;17), faggot cells, and DIC risk..

WHO 2022 classifies acute leukaemias primarily by lineage (AML vs ALL) and defining genetic abnormalities, moving away from pure morphology:

AML subtypes include: AML with recurrent genetic abnormalities (the cytogenetic entities below), AML with myelodysplasia-related changes, therapy-related AML, AML NOS.

ALL (now called B-lymphoblastic or T-lymphoblastic leukaemia/lymphoma): B-ALL subtypes defined by genetics (Philadelphia+, ETV6-RUNX1, hyperdiploidy, hypodiploidy); T-ALL is a separate entity.

FAB classification (French-American-British, 1976) uses morphology and cytochemistry to subtype:

FAB	AML Name	Key feature
M0	Minimally differentiated	MPO negative by light microscopy
M1	Without maturation	Some MPO+ blasts
M2	With maturation	t(8;21); Auer rods
M3	Acute promyelocytic (APL)	t(15;17); faggot cells; DIC risk
M4	Myelomonocytic	Mixed myeloid + monocytic
M4Eo	M4 + eosinophilia	inv(16)
M5	Monocytic	Gum hypertrophy; NSE+
M6	Erythroleukaemia	Predominant erythroid precursors
M7	Megakaryoblastic	Down syndrome association

FAB L1 (small blasts, children), L2 (large blasts, adults), L3 (Burkitt-like, now reclassified) for ALL.

For exams: know M2 (t(8;21), Auer rods) and M3 (APL, t(15;17), ATRA treatment, DIC) by heart.

Acute Myeloid Leukaemia (AML): Pathology and Cytogenetics

⚑ AI image — pending faculty review (auto-QA score 7/10; best of 3 attempts)

Three-panel medical diagram showing AML blast morphology with Auer rods, an APL faggot cell, and a color-coded AML cytogenetic prognostic classification table. — **Panel A:** AML blast with high N:C ratio, fine chromatin, prominent nucleolus, Auer rod, and normal RBCs for comparison.. **Panel B:** APL promyelocyte showing bundled Auer rods forming a faggot cell, with DIC risk highlighted.. **Panel C:** Color-coded AML cytogenetic-prognostic groups including t(15;17), t(8;21), inv(16), normal karyotype, FLT3-ITD, complex karyotype, chromosome 5/7 abnormalities, and TP53 mutation..

AML is predominantly a disease of adults (median age ~65 years), though it occurs at all ages.

Morphology:
• Blasts are large with high N:C ratio, prominent nucleoli, and fine chromatin.
• Auer rods — pathognomonic of AML. These are crystallised, fused primary granules that form needle-like pink inclusions in the blast cytoplasm on Romanowsky stain. A single Auer rod confirms myeloid lineage. In APL, bundles of Auer rods form faggot cells.

Peripheral blood smear showing AML blasts with Auer rods, APL faggot cell detail, and cytogenetic-prognostic classification table. — **Panel A:** Peripheral blood smear (Giemsa, 100×) showing blast nucleus, Auer rods as magenta needle-like inclusions, normal RBCs for comparison. **Panel B:** APL faggot cell with characteristic bundled Auer rods. **Panel C:** Cytogenetic-prognostic groups table showing chromosomal abnormalities, FAB classification, prognosis, and special features for major AML subtypes.

Key cytogenetic–prognostic groups in AML:

Abnormality	FAB	Prognosis	Special feature
t(15;17) — PML-RARα	M3 (APL)	Favourable with ATRA	DIC at presentation; ATRA differentiates the blasts
t(8;21) — RUNX1-RUNX1T1	M2	Favourable	Auer rods abundant; responds well to cytarabine
inv(16) — CBFB-MYH11	M4Eo	Favourable	Abnormal eosinophils in marrow
FLT3-ITD	Any	Poor	Common; targeted by midostaurin
Complex karyotype (≥3 abnormalities)	t-AML / MDS-related	Poor	Often therapy-related

Acute Promyelocytic Leukaemia (APL) — must-know:
The t(15;17) fuses PML with RARα, producing a fusion protein that blocks myeloid differentiation at the promyelocyte stage. The hypergranular promyelocytes release tissue factor and proteases → DIC (bleeding + clotting) is a life-threatening presentation. All-trans retinoic acid (ATRA) binds the PML-RARα fusion, overcoming the differentiation block → promyelocytes mature, blast count falls. ATRA + arsenic trioxide has turned APL from the most lethal to the most curable AML subtype.

CLINICAL PEARL

A patient with newly diagnosed AML who presents with simultaneous bleeding and thrombosis (purpura + limb ischaemia, or gum bleeding + DVT) should raise immediate suspicion for APL and DIC. Start ATRA empirically while awaiting FISH confirmation for t(15;17)—delay is dangerous. Check PT, aPTT, fibrinogen, and D-dimer immediately. This is one of the few haematological emergencies where treatment precedes cytogenetic confirmation.

Acute Lymphoblastic Leukaemia (ALL): Pathology and Cytogenetics

Four-panel medical diagram showing ALL lymphoblast morphology, lymphoid lineage origin, T-ALL convoluted nuclei, and major B-ALL cytogenetic subtypes with age groups and prognosis. — **Panel A:** ALL lymphoblasts with high N:C ratio, scant cytoplasm, smooth nuclear contours, inconspicuous nucleoli, absent cytoplasmic granules, Auer rods absent; AML myeloblast inset with granules and Auer rod for comparison.. **Panel B:** Hematopoietic stem cell, committed lymphoid progenitor, B-ALL 80-85%, T-ALL 15-20%.. **Panel C:** T-ALL blast with convoluted nucleus, scant cytoplasm, high N:C ratio.. **Panel D:** B-ALL cytogenetic subtypes: hyperdiploidy, ETV6-RUNX1 t(12;21), Philadelphia chromosome/BCR-ABL1 t(9;22), hypodiploidy; associated age group and prognosis..

ALL is the commonest malignancy of childhood (peak 2–5 years). Adult ALL carries a worse prognosis. ALL arises from committed lymphoid progenitors — either B-cell (80–85%) or T-cell (15–20%).

Morphology:
• Lymphoblasts are generally smaller than myeloblasts, with scant cytoplasm, inconspicuous nucleoli, and smooth nuclear contours.
• Cytoplasm lacks granules; Auer rods are ABSENT.
• In T-ALL, blasts may have a convoluted nucleus.

Microscopic blood smear showing ALL lymphoblasts with high nuclear-to-cytoplasm ratio alongside a table of cytogenetic subtypes and their prognoses. — **Panel A:** ALL lymphoblasts with high N:C ratio, scant cytoplasm, smooth nuclear contours; AML myeloblast inset for comparison. **Panel B:** Cytogenetic subtypes including hyperdiploidy, ETV6-RUNX1, Philadelphia chromosome, and hypodiploidy with age groups and prognoses.

Key cytogenetic subtypes in B-ALL:

Genetic finding	Age group	Prognosis	Note
Hyperdiploidy (>50 chromosomes)	Children	Excellent	~25% of childhood B-ALL; responds to methotrexate
ETV6-RUNX1 (TEL-AML1), t(12;21)	Children	Excellent	Commonest translocation in children; cryptic on standard karyotype, needs FISH
Philadelphia chromosome t(9;22) — BCR-ABL1	Adults	Poor (historically)	~25% of adult ALL; now treated with TKI (imatinib/dasatinib) + chemo
Hypodiploidy (<44 chromosomes)	Any	Very poor	Near-haploid: worst prognosis
MYC rearrangements (L3/Burkitt)	Any	Variable	Highly proliferative; separate protocol

T-ALL: Adolescent males; mediastinal mass (thymus involvement) causing SVC syndrome. Worse prognosis than favourable B-ALL but better than Ph+ B-ALL. Treated with augmented protocols.

Sanctuary sites in ALL:
• CNS: Leukaemic blasts cross the blood-brain barrier; CNS prophylaxis (intrathecal methotrexate ± cranial radiation) is mandatory.
• Testicular: Blasts in testicular parenchyma (blood-testis barrier); boys require testicular surveillance; testicular relapse can occur years after apparent remission.

SELF-CHECK

A 4-year-old boy is diagnosed with B-ALL. FISH shows ETV6-RUNX1 fusion and karyotype reveals 54 chromosomes. Which of the following BEST describes his prognosis?

A. Poor — Philadelphia-positive ALL has high relapse rate

B. Intermediate — hyperdiploidy alone is not favourable

C. Excellent — both hyperdiploidy and ETV6-RUNX1 are independently favourable markers

D. Cannot be determined without flow cytometry

Reveal Answer

Answer: C. Excellent — both hyperdiploidy and ETV6-RUNX1 are independently favourable markers

ETV6-RUNX1 (TEL-AML1) fusion and hyperdiploidy (>50 chromosomes) are the two most favourable cytogenetic findings in B-ALL. Each independently confers excellent prognosis, and their co-occurrence is considered doubly favourable. Philadelphia chromosome (t(9;22)) and hypodiploidy are the adverse markers to contrast with.