Acute Myelogenous Leukemia (AML)

 

Epidemiology and Etiology:

    •  Adults primarily
      • 15-39y peak
    • APL:
      • 35-40y median
    • M5:
      • Older patients
    • M6:
      • Older patients
    •  

 

Common sites:

    •  

 

Gross features:

    •  

 

Histologic features:

    • Bone marrow:
      • Blast count generally > 20%
        • But this is NOT required with presence of t(8;21), inv(16), t(16;16), or t(15;17)
    • Peripheral blood:
      • Myeloblasts
        • Large (15-20 um)
        • Very high n:c ratio (7:1 to 5:1)
        • Scant basophilic cytoplasm
          • Auer rods may be present  (30%) (diagnostic of acute non-lymphocytic leukemia)
            • This is an agglomeration of azurophilic (primary) granules
            • Peroxidase and sudan black B positive
          • Cytoplasmic granules may be present
        • Round to oval
        • Round to oval nucleus
        • Finely reticular chromatin
        • Distinct nucleoli (2-5)
      • Monoblasts:
        • Large
        • Abundant cytoplasm
          • Moderately to intensely basophilic
          • Pseudopod formation
        • Scattered fine azurophilic granules and vacuoles maybe
        • Round nuclei with delicate lacy chromatin
          • One or more large prominent nucleoli
      • Promonocytes:
        • Irregular and delicately convoluted nuclear configuration
        • Cytoplasm less basophilic, more granules and vacuoles sometimes
        •  
      • Pronormoblast (seen in acute erythroid leukemia or M6)
        • Large (17-24um)
        • Very high N:C ratio (8:1)
        • Finely reticulated (granular) chromatin
        • Prominent nucleoli (1 or more)
        • Scanty, pale blue cytoplasm with perinuclear halo
        • No granules
    • Revised FAB classification (note: doesn’t affect prognosis much)
      • MO – Minimally differentiated (2-3%)
        • No cytologic or cytochemical markers of myeloblasts (ex MPO negative)
        • Express myeloid lineage antigens
        • Ultrastructural features of myeloblasts
      • M1 – Without maturation (20%)
        • >= 3% of blasts are peroxidase positive
        • few granules or Auer rods
        • little maturation beyond myeloblast
      • M2 – With maturation (30-40%)
        • Full range of myeloid maturation
        • Auer rods present (most cases)
        • Often associated with t(8;21)
      • M3 – Acute promyelocytic leukemia (5-10%)
        • Most cells are hypergranular promyelocytes
          • Generally slightly larger than myeloblasts (12-24um)
          • High n:c ratio (5:1 to 3:1)
          • Blue cytoplasm with numerous coarse azurophilic granules
            • Bright pink, red or purple in Romanowsky stains
            • Hypogranular variant exists (microgranular)
          • Small perinuclear hoff may be present
          • Nucleus
            • Irregular and greatly variable
            • Often kidney-shaped or bilobed (butt-shaped)
          • Chromatin finely reticular with slight clumping
          • Distinct nucleoli (1-3)
          • Sultan bodies (faggot cells) are seen scattered in most cases of acute promyelocytic leukemia
          • Bundles of Auer bodies stacked together
        • Often many Auer rods per cell
        • High incidence of DIC
        • Strong association with t(15;17)
      • M4 – Acute myelomonocytic leukemia (15-20%)
        • Myelocytic and monocytic differentiation
        • Range of maturation in myeloid elements
        • Monoblasts are positive for nonspecific esterases
        • Subset associated with inv(16)
      • M5 – Acute monocytic leukemia (10%)
        • M5a – monoblasts (MPO neg, nonspecific esterase pos) and promonocytes predominate in marrow and blood
        • M5b – mature monocytes predominate in peripheral blood
        • Older patients
        • High incidence of organomegaly, lymphadenopathy, tissue infiltration
      • M6 – Acute erythroleukemia (5%)
        • Dysplastic erythroid precursors predominate
          • Some megaloblastoid
          • Others with giant or multiple nuclei)
        • >30% of non-erythroid cells are myeloblasts
        • advanced age
        • most are therapy-related
        • Pronormoblasts
          • Large (17-24um)
          • N:C ratio 8:1
          • Finely reticulated (granular) chromatin – somewhat clumpy – like a salami slice
          • Prominent nucleoli (1 or more)
          • Scanty, pale blue, agranular cytoplasm
          • Dim CD45 on flow
        • Erythroid “gigantoblasts”
          • Hyperlobated nuclear features
          • “block” pattern of PAS reactivity (normal erythroid cells are PAS negative)
      • M7 – Acute megakaryocytic leukemia (1%)
        • Megakaryocytic blasts predominate
          • Blebs coming off of cytoplasm (like platelets)
          • Positive for platelet-specific immunos (GPIIb/IIIa, vWF)
        • Myelofibrosis or increased marrow reticulin in most cases
      • FAB M8 (basophilic):
        • Cells have coarse basophilic granules
    • Multilineage dysplasia fits criteria for AML with myelodysplasia-related changes

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 CD13

 

 

CD33

 

 

CD15

 

 

CD34

Negative in promyelocytic

 

DR (differentiated cells)

 

 

MPO

(by cytochemistry or immunohistochemistry)

(negative in M0)

(always strong in APL – hyper or hypogranular)

(often negative in monoblastic)

 

Non-specific esterase

(red-brown staining) (monocytoid cells and precursors)

APL – weak in 25%

 

PAS

(erythroid, megakaryocytoid, some lymphoid)

 

 

CD117

 

 

CD65

 

 

Glycophorin C (erythroid lineage including blasts)

 

 

CD61

(megakaryocytes and precursors)

 

 

 

Molecular features:

    • Acute leukemia testing guidelines
    • most involve acquired genetic alterations that inhibit terminal myeloid differentiation
    • Balanced translocations create chimaeric protein that is required but usually not sufficient for leukaemogenesis
      • RT-PCR has a higher sensitivity than cytogenetic analysis
    • Normal karyotype (NK) (20-30% pediatric, 40-50% of adult):
      • Intermediate prognosis?
      • See mutations listed below
      • Cytogenetic abnormalities that may go undetected in suboptimal preparations:
        • inv(3)(q21q26)
        • t(6;9)(p22;q34)
        • t(6;11)(q27;q23)
        • t(9;11)(p21;q23)
        • t(11;19)(q23;p13)
        • inv(16)(p13q22)
      • cryptic abnormalities:
        • t(5;11)(q35;p15)
    • +8 (trisomy 8) (15% of cytogenetically abnormal AML – 5% sole abnormality)
      • most common chromosomal abnormality in AML
      • frequent as a secondary change
      • unknown functional / molecular genetic consequence
      • not sufficient for leukemogenesis (but sole cytogenetic abnormality in 5%)
      • intermediate prognosis as a sole change
      • polysomy 8: (tetrasomy, pentasomy, hexasomy)
        • relatively rare
          • only 18 reported cases as a sole anomaly
        • AML, MDS, MPD
        • MLL rearrangements in a substantial number (~16%)
          • Maybe you should r/o cryptic MLL rearrangement in polysomy 8 as sole anomaly
        • myelomonocytic or monocytic component often (M4, M5) (55%)
        • poor prognosis / high risk (sole or part of complex)
    • -7 / del(7)(q) (poor prognosis) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
      • Common secondary change
        • There is a clear association between 3q26 rearrangements / EVI1 expression and monosomy 7
        • Note that presence of del(7)(q) with inv(16) does not confer a poor prognosis
      • Adults usually
        • 5% of pediatric AML
      • Clear association with previous genotoxic treatment
        • Alkylators
        • radiotherapy
      • Associated with significant occupational exposures to potential carcinogens (benzene, smoking)
        • May be a marker of mutagen-induced hematological malignancies
      • Most frequent cytogenetic abnormality detected in myeloid neooplasms with constitutional predisposition:
        • Fanconi anemia
        • neurofibromatosis type I
        • severe congenital neutropenia
      • Morphology:
        • Often unclassifiable, or in decreasing order of frequency, M6,M0,M1,M7
      • Immunophenotype:
        • CD7, CD13, CD15, CD18, CD33, CD34
      • Prognosis:
        • Adverse prognostic impact
          • Poor response to chemotherapy
          • Dismal outcome
      • Monosomy 7 (10% of cytogenetically abnormal AML) (5% as sole change)
        • Found with other changes
          • -5/del(5)(q)
          • -17
        • Often not a true whole chromosome loss
          • Complex rearrangements often
        • Pathogenetically important molecular genetic consequence of monosomy 7 is unknown
        • Association with diabetes insipidus
      • del(7)(q) (5% of cytogenetically abnormal AML) (1% as sole change)
        • if sole change, often subclones with +8 are present
        • marked heterogeneity in breakpoints
        • several interstitial regions have been implicated, mainly:
          • 7q22
          • 7q32q33
        • Concluded that loss of several genes rather than of a signle tumour suppressor gene is the pathogenetically important outcome
          • Target genes remain elusive
    • +21 (5% of karyotypically abnormal AML) (1% as a sole anomaly)
      • 2nd most common trisomy
      • Usually (80%) present with other aberrations
        • +6, -7, +8, +19, +22
        • Secondary change to inv(16)/t(16;16)
      • Some (but not most) are associated with mutations in the runt domain or RUNX1, in 2 of 3 copies, suggesting duplication of the mutated 21
      • Prognosis is debatable; intermediate or unfavorable
    • -5 (5% of cytogenetically abnormal AML) / del(5)(q) (5-10% of cytogenetically abnormal AML) (40% of t-AML) (poor prognosis)
      • sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML
      • Significantly more common in t-AML than in de novo AML
      • Associated with significant occupational exposures to potential carcinogens
        • May be a marker of mutagen-induced hematological malignancies
      • -5 is almost exclusively present with other abnormalities (only 10 reported cases otherwise); del(5)(q) is most often present with other abnormalities (but relatively often sole abnormality)
        • -7/del(7)(q)
        • -17/del(17)(p)
        • -18
        • del(5)(q) only:
          • inv(3)/t(3;3)
          • t(9;22)
      • variable proximal and distal breakpoints
        • critical genes and pathogenesis has not been determined
          • 5q31 is most commonly involved
          • EGR1, RPS14, CTNNA1 may be involved in “5q- syndrome”
        • many cases may actually be unbalanced translocations (even monosomy 5s)
      • FAB M0 and M6 often with complex karyotypes
      • CD2, CD7, CD13, CD14, CD15, CD18, CD33, CD34
      • poor prognosis
        • resistance to chemotherapy
      •  (2-3% of karyotypically abnormal AML)
      • Sole change in 25% of those
      • Generally not associated with any characteristic AML-related translocations or inversions
        • Exceptions: t(6;9)(p22;q34), t(8;16)(p11;p13)
      • Associated with increased FLT3 (13q12) expression
        • Not associated with FLT3 ITD mutations
      • Associated with RUNX1 mutations (almost all cases in one study)
      • Elderly males (most)
        • SR 2.5
        • Median 65 y
      • No previous genotoxic treatment
      • Marked leukocytosis
      • Thrombocytopenia
      • M0 or M1 usually
        • Most FAB types have been reported
      • Trilineage dysplasia typically
      • Low complete remission rate and brief remission duration
    • +11 (trisomy 11) (2-3% of cytogenetically abnormal AML) (sole change in 40%):
      • Often occurs with other numerical anomalies
      • Unknown biological effect
      • Sole abnormality:
        • ITD of MLL in a substantial proportion (25-90%) of trisomy 11 as sole abnormality
        • Middle aged and elderly
        • De novo mostly (no prior therapy)
        • Prior MDS phase  often
        • Trilineage dysplasia often
        • M1,M2,M4, often with Auer rods
        • HLA-DR,CD13,CD15,CD33,CD34
        • Poor response to chemotherapy and unfavorable prognosis in most studies
          • Particularly dismal with ITD of MLL and/or FLT3
    • +13 (2-3% of karyotypically abnormal AML) (25% as sole)
      • Occurs with mainly numerical abnormalities
        • Not usually with any characteristic AML-related translocations or inversions
          • Excepting t(6;9)(p22;q34) or t(8;16)(p11;p13)
      • FLT3 gene on 13q12
        • Increased FLT3 expression in almost all cases
      • RUNX1 mutations in almost all cases
      • Elderly males mostly (SR 2.5, median age 65)
      • No previous genotoxic treatment mostly
      • Marked leukocytosis and thrombocytopenia
      • Morphologically heterogeneous
        • M0 or M1 in a substantial proportion
      • Frequent expression of myeloid as well as lymphoid antigens
      • Small blasts with few or no granules typical
      • Hand-mirror blasts typical
      • Lack of Auer rods typical
      • Trilineage dysplasia typical
      • Low complete remission rate in all studies
      • Brief remission duration in all studies
    • +22 (2-3% cytogenetically abnormal AML) (only 10% as sole abnormality)(1% of MDS) (5% of ALL)
      • Occurs with other abnormalities (90%)
        • +8
        • +19
        • +21
        • Inv(16)(p13q22)
          • Should be suspected in any case with +22 as sole abnormality (several studies support this)
      • As a sole abnormality (10%):
        • Rule out inv(16)
        • M > F (2.1:1)
        • Young adults (30y median)
        • Prognosis has not been adequately studied
          • Intermediate or unfavorable prognosis group
      • No known mutation on 22 associated as of yet
    • +4 (trisomy 4) (1% of all cytogenetically abnormal AML) (sole in 1/3)
      • Association with dmin (MYC-containing), sometimes as a subclone or in a separate clone
      • Common secondary change to t(8;21)(q22;q22)
      • Unknown molecular genetic consequences
        • Most studies have focused on KIT at 4q12
        • Associateion with KIT mutations
      • Sole change:
        • Adults (median age 55y) primarily
        • M2 or M4 mostly
        • Mainly de novo (not treatment related)
        • Marked leukocytosis possibly
        • Extramedullary leukemia possibly
        • Hand-mirror appearance of blasts possibly
        • Poor outcome compared to others in intermediate risk group (review of 30 cases)
    • t(8;21) (q22;q22) (good prognosis; intermediate with KIT mutation) (5%)
    • inv(16)(p13.1q22) or t(16;16)(p13.1;q22) (good prognosis; intermediate with KIT mutation) (5-8%) – aka AML with abnormal marrow eosinophils
    • t(15;17)(q22;q12) (APL) (5-8%) (good prognosis)
    • t(9;11)(p22;q23); MLLT3-MLL (intermediate prognosis)
    • Other MLL translocations (11q2.3) (poor prognosis)
      • Over 80 translocations described in acute leukemia
        • Over 50 partner genes characterized
      • Up to 1/3 of MLL translocations in AML are not seen in karyotype, requiring FISH or other molecular studies
      • Translocations that commonly result in AML (but also seen in ALL):
        • MLLT1 (ENL) (LTG19) – 19p13.3 – eleven nineteen leukemia
        • MLLT10 (AF10) – 10p12 – ALL1 fused gene from chromosome 10
        • MLLT4 (AF6) – 6q27 – ALL1 fused gene from chromosome 6
        • ELL (MEN) – 19p13.1 – myeloid eleven nineteen translocation (unrelated to MEN1 or MEN2)
      • Some studies indicate poor prognosis
      • Other studies indicate t(9;11)(p22;q23) (MLL/AF9) have favorable or standard prognosis
        • And that t(10;11)(p12;q23) (MLL/AF10) have favorable or standard prognosis
        • Both these tend to be younger with M5 classificaiton
      • Associated histology:
        • Monocytoid
    • t(9;22)(q34;q11) (bcr/abl) (1-3% of adults) (poor prognosis)
      • ?same as myeloid blast crisis in CML
    • t(6;9)(p23;q34) (DEK-NUP214) (0.7-1.8%) (poor prognosis)
    • inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 (1-2%)
    • t(1;22)(p13;q13); RBM15-MKL1 (OTT-MAL) (<1%) (2-3% of children)
    • t(3;12)(q26;p13)
      • ETV6-EVI1
      • Adults (vast majority)
      • Prior MDS that often rapidly progresses to AML
      • Variable morphology (often unclassifiable)
      • Dysplastic megakaryotcytes
      • Normal or decreased platelets
      • Dismal prognosis
    • t(4;12)(q12;p13)
      • CHIC2(BTL)-ETV6
        • Breakpoint heterogeneity at 4q12
        • Dysregulation of other genes in 4q12 may be the more important mechanism
          • GSX2 is a candidate
      • Sole abnormality in 70%
      • Secondary abnormalities:
        • -7
        • -11
        • i(17)(q10)
      • Adults mostly
        • Median age 60 y.
      • M0,M1, or unclassifiable mostly
      • Trilineage dysplasia
      • Lymphoid-like morphology of blasts
      • Absent or low myeloperoxidase activity
      • Basophilia
      • Myeloid immunophenotype with frequent aberrant CD7
      • Unfavorable prognosis
    • t(7;12)(q36;p13)
      • very difficult to identify cytogenetically
      • rarely the sole cytogenetic change
        • trisomy 19 also with few exceptions
        • trisomy 8
        • therefore infant AML with the above 2 should be tested for t(7;12)
      • MNX1-ETV6
        • Some cases don’t directly involve MNX1
        • Aberrant expression of MNX1 may be the functionally important outcome
      • Infant (almost exclusively)
      • 2nd most common rearrangement after 11q23 changes in this age group
      • Variable morphology
        • Poorly differentiated (M0 or M1)
      • Very poor outcome
    • 11p15 rearrangements (1% of karyotypically abnormal cases):
      • Translocations mainly
        • t(5;11)(q35;p15)
        • t(7;11)(p15;p15)
        • t(11;20)(p15;q12)
        • others
      • Inversions
        • inv(11)(p15q22)
        • others
      • Insertions
      • Often sole anomaly (60%)
        • Secondary changes: +8,-18,-7,-5,-17
      • Clinical ramifications unknown due to rarity of individual abnormalities
      • NUP98 (11p15) involved in 10-35%
        • 5’NUP98 is important half
        • HOX family is common partner
    • del(12)(p) (12p rearrangements found in 5% of cytogenetically abnormal AML) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
    • del(9)(q) (3%) (sole abnormality in 1/3 of those) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
      • 9q21 contains a commonly deleted 2.4 Mb region
        • Haploinsufficiency of several genes located here may be the leukemogenic mechanism
        • Mutations in these genes have not been identified
      • Also reported as a single anomaly in a few MDS and MPD cases
      • Interstitial deletion
      • Sole abnormality (rare):
        • Association with CEBPA mutations (~50% of del(9)(q))
        • Adults (50y median)
        • M2 morpholgy > M1, M4 > others
        • Immunophenotype:
          • HLA-DR, CD15, CD33, CD34, CD7
        • Intermediate cytogenetic risk group
    • del(20)(q) (1-2% of cytogenetically abnormal AML, sole abnormality in 1/3 of those)
      • not specific for AML
        • more common in MPN and MDS
      • may not be sufficient for leukemogenesis
        • have been used successfully in BM transplants
        • has been observed in patients with morphologically normal BM and without cytopenia
      • associated cytogenetic changes:
        • -5/del(5)(q)
        • -7/del(7)(q)
        • +8
        • -17
        • -18
      • Not a common secondary change to AML-associated translocations/inversions
      • As a sole cytogenetic abnormality:
        • M:F = 1.7:1
        • Adults mainly (median 60 y)
        • FAB subtype not characteristic
        • De novo mostly
        • Prognosis:
          • Unclear; intermediate or unfavourable
          • not favourable as it is in MDS
      • Interstitial, not terminal
      • L3MBTL gene has been implicated
    • i(17)(q10) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
    • 17p deletion (unbalanced translocation) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
    • -13/13q- (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
    • 11q- (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
    • idic(X)(q13) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
    • Complex karyotype:
    • Rare translocations:
      • t(1;3)(p36.3;q21.1) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML) (poor prognosis)
        • sole abnormality in ~75 %
        • additional changes:
          • -2
          • 5q-
        • RPN1 at 3q21
          • Ribophorin 1
        • 1p36 breakpoints vary extensively
          • Molecular consequences of t(1;3) seem to be heterogeneous
          • PRDM16 (MEL1) at 1p36
            • PR domain containing 16
            • Encoding a zinc finger protein homologous to MDS1/EVI1
            • Transcriptionally activated by RPN1
        • M4 mostly
        • Adults mostly (median 60 y.)
        • Prior genotoxic exposure in 10-15 %
          • Radiotherapy and alkylating agents rather than topoisomerase II inhibitors
        • MDS, AML
          • MDS phase often short
          • Trilineage dysplasia
            • Dyserythropoiesis and a marked dysmegakaryocytopoiesis
        • Dismal outcome
          • Most cases virtually nonresponsive to conventional chemotherapy
      • t(2;11)(p21;q23) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
        • most commonly occurs in therapy-related disease
      • t(3;5)(q25;q35) (sole in 80 %) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
        • t(3;5)(q21-25;q31-35)
        • median 30 y (younger adults)
        • association with Sweet syndrome
        • plt counts usually low
        • M6 preponderance but morphologies can be seen
        • Increased micromegakaryocytes
        • Prior MDS phase with Trilineage dysplasia
        • variable breakpoints
          • t(3;5)(q21;q31) and t(3;5)(q25;q34) are most common
          • t(3;5)(q25;q34) was determined to be in all cases in one study
        • initial prognosis was determined as poor, but several long-term survivors have been identified
        • MLF1 at 3q25 and NPM1 at 5q35
          • MLF1 has been shown to inhibit erythropoietin induced differentiation
        • Chimeric protein that is transported to the nucleus and expressed at high levels maingly in the nuclolus
      • t(3;21)(q26.2;q22.1) (poor prognosis) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
        • CML (more common), AML, MDS, MPD
        • Adults mainly (median 60 y)
        • Treatment-related (t-AML) (50%)
          • Strongly correlated with previous topoisomerase II poisons
        • Morphology unclassifiable mostly
          • Some are M2 or M4
        • RUNX1 (AML1) at 21q22
          • Promotor region and RUNX1 sequences moved to the der(3)
        • 3 genes on 3q26 involved in a complex rearrangement resulting in a chimeric protein:
          • EVI1
          • MDS1
          • RPL22P1 (EAP)
        • Secondary changes:
          • -7
          • +8
          • +12
          • +der(21)
        • Poor prognosis by most investigators
      • t(5;7)(q33;q11.2) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
      • t(5;10)(q33;q21) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
      • t(5;12)(q33;p12) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
      • t(5;17)(q33;p13) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
      • t(11;16)(q23;p13.3) (sufficient for Dx of AML with myelodysplasia-related features unless it is t-AML)
        • most commonly occurs in therapy-related disease
    • Gene mutations:
      • In absence of karyotypic abnormality, FLT3, NPM1, and CEBPA mutations (alone or in combination) have prognostic significance in the context of most current therapies
      • Fms-related tyrosine kinase 3 (FLT3) (13q12) (20-40%)
        • Tyrosine kinase receptor involved in hematopoietic stem cell differentiation and proliferation
        • Occur in any AML type and in MDS
          • Most common with t(6;9)(p23;q34), APL, and AML with a normal karytype
          • May also occur with other so-called cooperating mutations
        • 2 primary types of mutations:
          • Internal tandem duplications (FLT3-ITD) within the juxtamembrane domain (75-80%)
          • Codons 835 and 836 of the second tyrosine kinase domain (TKD) (20-35%)
        • Prognosis:
          • FLT3-ITD mutations with normal cytogenetics are associated with poor prognosis
          • FLT3-TKD mutations remain controversial
      • Nucleophosmin (NPM1) (1/3 of adult AML) (good prognosis with a normal karyotype and absence of FLT3-ITD)
        • Exon 12 usually
        • ~40 mutation variants described
          • TCTG tetranucleotide duplication at positions 956 to 959 accounts for 70-80%
          • All variants result in aberrant localization of NPM to the cytoplasm (rather than nucleus)
        • Prognosis:
          • Favourable in AML with a normal karyotype (in the absence of FLT3-ITD)
        • Association with certain morphologic and clinical features
        • Cytoplasmic NPM by immunohistochemistry correlates well with the presence of mutations by PCR
      • CEBPA (6-15%)
        • CCAAT/enhancer binding protein-alpha
          • Transcription factor involved in control of proliferation and differentiation of myeloid progenitors
        • Usually biallelic mutations
        • Two general categories:
          • Out-of-frame insertions and deletions in the N-terminal region
          • In-frame insertions and deletions in the C-terminal region
        • Prognosis:
          • Favourable in AML with a normal karyotype (in the absence of FLT3-ITD)
        • Association with certain morphologic and clinical features
      • KIT (4q11-12)
        • Member of the type III tyrosine kinase family
        • Transmembrane glycoprotein
        • Exon 8 and 17 most commonly
        • Gain of function mutations also occur in:
          • GIST
          • GCTs
          • Mastocytosis
        • Prognosis:
          • Poor prognosis among AML with t(8;21)(q22;q22) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22)
      • MLL
        • Less compelling evidence for prognostic significance of mutation
        • Partial tandem duplication in 5-10% of adults with a normal karyotype or isolated trisomy 11
          • Adverse prognosis, eliminated in patients receiving an autologous stem cell transplant in first remission
      • WT1
        • Poor prognosis with a normal karyotype
      • NRAS
        • Less compelling evidence for prognostic significance
      • KRAS
        • Less compelling evidence for prognostic significance
      • RUNX1
        • Runt domain mutations are common in M0
      • JAK2 V617F (3%)

 

Other features:

    • Heterogenous group
    • clinical features:
      • anemia
      • neutropenia
      • thrombocytopenia
    • APL
      • DIC frequently
      • treated with retinoic acid to overcome the block in differentiation
        • prognosis better than for any other AML cytogenetic subtype
        • refractory cases generally respond well to arsenic trioxide therapy
      • EM:
        • Auer rods - hexagonal arrangement of tubular structures with a specific periodicity of ~250 mm in contrast to the 6-20 laminar periodicity of Auer rods in other types of AML.

 

References:

    • Swerdlow. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. WHO Publications; 2008.
    • Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004:1552.
    • Heim S, Mitelman F. Cancer Cytogenetics. 3rd ed. Wiley-Blackwell; 2009.
    • CAP; Color Atlas of Hematology; 1998
    • Abdou SMH, Jadayel DM, Min T, et al. Incidence of MLL rearrangement in acute myeloid leukemia, and a CALM-AF10 fusion in M4 type acute myeloblastic leukemia. Leuk. Lymphoma. 2002;43(1):89-95.
    • Beyer V et al.  Polysomy 8 defines a clinico-cytogenetic entity representing a subset of myeloid hematologic malignancies associated with a poor prognosis: report on a cohort of 12 patients and review of 105 published cases.  Cancer Genetics and Cytogenetics 160 (2005) 97–119.
    • NCCN Guidelines version 1.2011 for Acute Myeloid Leukemia