Morphology and Genetics: Quick Correlation in Acute Myeloid Leukaemia (WHO 5th Edition), with Summary Table and MCQs

Subtitle: A quick morphology-genetics correlation for acute myeloid leukaemia with defining genetic abnormalities (WHO 5th edition, 2022): APL, RUNX1::RUNX1T1, CBFB::MYH11, NPM1, CEBPA, DEK::NUP214, RBM15::MRTFA, KMT2A, MECOM, NUP98, BCR::ABL1 and KAT6A::CREBBP, with a summary table and 8 MCQs.

Author: PathologyMCQ Editorial Board

Category: Haematopathology

Last Updated: October 2026

Read Time: 7 minutes

At-a-Glance

Long slender Auer rod + perinuclear hof: t(8;21) RUNX1::RUNX1T1.
Abnormal purple-granuled eosinophils: inv(16) CBFB::MYH11.
Cup-like nuclei: NPM1 (often with FLT3-ITD).
Erythrophagocytosis: t(8;16) KAT6A::CREBBP, not CEBPA.
Basophilia + dysplasia: t(6;9) DEK::NUP214. Small monolobated megakaryocytes: inv(3) MECOM.
WHO 5th edition drops the 20% blast threshold for most genetically defined AMLs, except BCR::ABL1 and CEBPA.

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WHO 5th Edition Categories

The WHO Classification of Haematolymphoid Tumours, 5th edition (2022), splits AML into AML with defining genetic abnormalities and AML defined by differentiation. The first group includes APL with PML::RARA, AML with RUNX1::RUNX1T1, CBFB::MYH11, DEK::NUP214, RBM15::MRTFA, BCR::ABL1, KMT2A rearrangement, MECOM rearrangement, NUP98 rearrangement, NPM1 mutation, CEBPA mutation, AML myelodysplasia-related, and AML with other defined genetic alterations (for example KAT6A::CREBBP, t(8;16)). For most of these the diagnosis no longer needs 20% blasts; BCR::ABL1 and CEBPA still require at least 20%.

Each genetic group has morphological clues. Some are specific enough to prompt the right test on the day the smear is seen.

Acute Promyelocytic Leukaemia with PML::RARA

Hypergranular: abnormal promyelocytes with bilobed or kidney-shaped nuclei, dense azurophilic granules, bundles of Auer rods (faggot cells).
Microgranular (hypogranular): bilobed or butterfly nuclei, inconspicuous granules, high white cell count; easily mistaken for monocytic leukaemia.
Immunophenotype: CD33 bright, CD13+, CD34 and HLA-DR negative, CD117 often weak; microgranular cases may express CD2 and CD34.
Clinical: disseminated intravascular coagulation; medical emergency; ATRA and arsenic trioxide.

Core-Binding Factor AML

AML with RUNX1::RUNX1T1, t(8;21)

AML with maturation. Blasts are large with abundant basophilic cytoplasm, a perinuclear hof and salmon-pink granules; some contain pseudo-Chédiak–Higashi granules. Auer rods are frequent and appear as a single long, slender rod with tapered ends. Dysplastic neutrophils with homogeneous pink cytoplasm are common. Blasts often express CD19, PAX5 and CD56; KIT mutations worsen the otherwise favourable prognosis.

AML with CBFB::MYH11, inv(16) or t(16;16)

Usually myelomonocytic with abnormal eosinophil precursors whose granules are large, dark purple-violet rather than orange; they are aberrantly chloroacetate esterase positive. Favourable prognosis, again modified by KIT mutations.

NPM1 and CEBPA

AML with NPM1 mutation

Blasts with cup-like nuclear invaginations (more than 25% of the nuclear diameter) in over 10% of blasts are highly suggestive, particularly with concurrent FLT3-ITD. Morphology is often myelomonocytic or monocytic. Blasts are usually CD34 negative, and cytoplasmic NPM1 on immunohistochemistry is a surrogate for the mutation.

AML with CEBPA mutation

Now defined by in-frame bZIP mutations (single or biallelic). Morphology is AML with or without maturation; blasts frequently express CD7 and HLA-DR. There is no specific morphological hallmark. Erythrophagocytosis, sometimes misattributed to CEBPA, is the classic clue to t(8;16) KAT6A::CREBBP.

Erythrophagocytosis in AML — Erythrophagocytosis by blasts: think t(8;16) KAT6A::CREBBP.

Other Fusions and Rearrangements

RBM15::MRTFA, t(1;22): infants; acute megakaryoblastic leukaemia with blasts that have agranular basophilic cytoplasm and cytoplasmic blebs; marrow fibrosis.
DEK::NUP214, t(6;9): AML with maturation or myelomonocytic; basophilia in blood and marrow; multilineage dysplasia; FLT3-ITD in most; poor prognosis.
KMT2A rearrangement: 11q23; monocytic, monoblastic or myelomonocytic; also therapy-related after topoisomerase II inhibitors.
MECOM rearrangement, inv(3)/t(3;3): variable blast morphology; small monolobated megakaryocytes, normal or raised platelets, multilineage dysplasia; very poor prognosis.
NUP98 rearrangement: cryptic, mainly paediatric (NUP98::NSD1 with FLT3-ITD); no specific morphology.
BCR::ABL1: de novo AML, needs 20% blasts; exclude CML blast phase.
KAT6A::CREBBP, t(8;16): monocytic blasts with erythrophagocytosis, DIC; often therapy-related.
AML, myelodysplasia-related: defined by MDS-type cytogenetics or mutations (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) or a prior MDS/MDS-MPN, not by morphology alone.

AML with RBM15::MRTFA fusion: megakaryoblasts with blebs.

Summary Table

Morphology to genetics in AML

Clue	Think of	Confirm with
Bilobed nuclei, heavy granules, faggot cells, DIC	APL, PML::RARA	PML IHC pattern, FISH, RT-PCR
Perinuclear hof, long slender Auer rod, pseudo-Chédiak–Higashi granules	t(8;21) RUNX1::RUNX1T1	Karyotype, FISH; CD19/CD56
Eosinophils with purple-violet granules	inv(16) CBFB::MYH11	FISH or RT-PCR (inversion can be cryptic)
Cup-like nuclei, CD34 negative	NPM1 mutation	NPM1 IHC (cytoplasmic), sequencing; check FLT3
Erythrophagocytosis by blasts	t(8;16) KAT6A::CREBBP	Karyotype, FISH
Basophilia, dysplasia	t(6;9) DEK::NUP214	Karyotype; FLT3-ITD
Small monolobated megakaryocytes, normal platelets	inv(3)/t(3;3) MECOM	Karyotype, FISH
Megakaryoblasts with blebs in an infant	t(1;22) RBM15::MRTFA	Karyotype, FISH
Monocytic blasts in a treated patient	KMT2A rearrangement	FISH break-apart

Test Yourself: 8 MCQs

AML morphology and genetics: 8 MCQs

Match the smear to the fusion or mutation, with instant explanations.

Score: 0 / 8

More practice: the question banks →

Exam Pearls

Morphology prompts the test; genetics makes the diagnosis.
APL: CD34−, HLA-DR−, DIC, start ATRA on suspicion.
CBF leukaemias are favourable; KIT mutation downgrades them.
NPM1: cup-like nuclei, cytoplasmic NPM1, CD34−; prognosis depends on FLT3-ITD.
Erythrophagocytosis = t(8;16). Basophilia = t(6;9). Monolobated megakaryocytes = inv(3).

For more concise notes, see the Concise Hematopathology Notes →

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