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

aka AML with abnormal marrow eosinophils

Epidemiology and Etiology:

· 5-8% of cytogenetically abnormal AML

· 95% are inversion, 5% are translocation

· younger patients predominantly

· vast majority are de novo rather than treatment related (< 5%)

Common sites:

·

Gross features:

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Histologic features:

· majority are FAB M4Eo (AML with bone marrow eosinophilia)

· also seen in other M4 and M5

· monocytic and granulocytic differentiation usually

· blasts often at 20% or lower

· characteristically abnormal eosinophil component in the BM (most cases)

· variable in number (usually increased, but sometimes < 5%)

· all stages of differentiation

· striking immature eosinophilic granules evident at the promyelocyte and myelocyte stages mainly

· larger

· purple-violet

· obscure the cell morphology in some cells

· nuclear hyposegmentation in mature eosinophils maybe

· naphthol-ASD-chloroacetate esterase reaction characteristically faintly positive in abnormal eosinophils (normally neg)

· neutrophils in BM usually sparse

· PB no different than other cases of AMML

· Eos not usually increased

· monocytoid by NSE stain and flow

· lobated blasts

· more strongly CD45

·

Immunophenotype:

Marker:

Sensitivity:

Specificity:

• complex with multiple blast populations
• immature blasts with high CD34 and CD117
• populations differentiating towards granulocytic (CD13, CD33, CD15, CD65, MPO)
• monocytic (CD14, CD4, CD11b, CD11c, CD64, CD36, lysozyme)
• maturation asynchrony often
• coexpression of CD2 with myeloid markers often (not specific)

Molecular features:

· CBFB/MYH11 fusion transcripts

· involve the core binding factor Beta gene (CBF-Beta) on 16q22 and the smooth muscle heavy chain (MYH11) on 16p13.1

· CBFB is a transcription factor that binds to enhancers of T-cell receptor, cytokine genes, and others

· Heterodimerizes with CBFA (gene product of RUNX1)

· Subtle rearrangements that may be overlooked on G-banding

· Additional abnormalities of the inv(16), often translocations, are not uncommon

· can be quantitated by Q-RT-PCR

· secondary genetic changes (40%):

· KIT mutations (30%)

· +22, +8 (10-15% each)

· Trisomy 22 is quite specific for inv(16) patients

· Trisomy 8 is not specific

· Del(7)(q) (6%)

· +21 (~5%)

· t(9;22)(q34;q11.2) (rare, usually seen in blast phase of CML)

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Other features:

· Favourable prognosis (irrespective of additional changes):

· longer complete remissions when treated with high dose cytarabine in the consolidation phase

· older patients have decreased survival

· those with KIT mutations have a higher risk of relaplse and worse survival

· those with +22 have been reported to have improved outcome

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References:

· Swerdlow. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. WHO Publications; 2008.

· Heim & Mitelman. Cancer Cytogenetics (2009)