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Leukemia - Acute

Recurrent genetic abnormalities

AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11

Reviewer: Syed Zaidi, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update September 2012
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

General
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● 5-8% of all cases of adult AML
● Associated with more frequent hepatosplenomegaly, lymphadenopathy and granulocytic sarcoma than AML in general
● Longer median survival than other AML (Am J Clin Pathol 2003;119:672); when treated with high dose cytarabine in consolidation phase, complete remission rates are 76%-92%
● If translocation present, consider as AML even if initial blast count is < 20%
● FISH recommended if suggestive cell morphology, but negative cytogenetics (J Mol Diagn 2004;6:271)
● Poor prognostic factors: high initial white blood cell count (for complete response); age > 35 years (for disease free survival, Blood 2003;102:462); older patients with KIT mutation for higher risk of relapse
● Peripheral blood: monocytosis, high blast counts

Micro description
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● Usually features of AML M4 (acute myelomonocytic leukemia) plus marrow eosinophilia, with dysplastic eosinophils containing large basophilic staining granules, especially in promyelocyte and myelocyte stages, less evident at later stages of eosinophil maturation (Am J Clin Pathol 2003;120:236)
● Granules are large, purple-violet, may obscure cell morphology
● Few mature abnormal eosinophils show faint staining with naphthol ASD chloroacetate esterase (negative in normal eosinophils); blasts have few Auer rods

Micro images
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Bone marrow smears (Wright-Giemsa):
       
Various images (some images associated with cytogenetic changes)

       
Eosinophil precursors show prominent basophilic staining granules

       
H&E, cytogenetics and FISH   H&E, RT-PCR and FISH


Immature cells with folded monocytoid nuclei mixed
with abnormal eosinophils (arrow), containing large
basophilic granules and more normal eosinophil granules

Virtual slides
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Bone marrow smear-AML with inv(16)

Positive stains
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● Granules are positive for chloroacetate esterase and nonspecific esterase
● High Ki-67, CBFbeta-SMMHC (nuclear stain with microgranular or fine-speckled pattern, Am J Surg Pathol 2006;30:1436)

Molecular description
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● Inversion(16) much more common than t(16;16)(p13;q22), but both cause fusion of CBFβ to MYH11
● Smooth muscle myosin heavy chain gene (SMMHC) produces MYH11 at 16p13.1; core binding factor beta (CBF-β) gene produces CBFβ at 16q22; fusion gene is CBFβ - MYH11 protein (Science 1993;261:1041, Proc Natl Acad Sci USA 1998;95:11863)
● May need FISH and RT-PCR to document the genetic alteration, because the rearrangement is subtle and easily overlooked in metaphase preparation
● Trisomy 22 is fairly specific for inv(16); mutations of KIT are seen in 30% of patients
● Multiple fusion transcripts exist (J Mol Diagn 2004;6:22); fusion transcripts appear to upregulate NF-kappaB signaling pathway (Mod Pathol 2007;20:811)

Molecular images
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Two G banded chromosomes,      Diagram
show pericentric inversion at #16,
arrowheads point to breakpoints
on abnormal chromosome

End of Leukemia - Acute > Recurrent genetic abnormalities > AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11

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