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Leukemia - Acute

Recurrent genetic abnormalities

Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARα

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


● Either hypergranular (this section) or microgranular / hypogranular
● 5-8% of AML cases
● Formerly called AML M3
● Median age 35-40 years, but can occur at any age
● Decreased WBC count (hypergranular variant) at presentation with abnormal promyelocytes
● Usually disseminated intravascular coagulation (DIC) and hemorrhage before or during induction chemotherapy, which may cause early death
● Rarely organomegaly, extramedullary disease, skin involvement (detect with FISH, Mod Pathol 2005;18:1569)
Criteria for diagnosis: most cells (> 50%) are abnormal promyelocytes with heavy cytoplasmic granulation that may obscure the nuclear cytoplasmic margin, often reniform or bilobed nucleus; cells with multiple Auer bodies usually present; also bundles of Auer rods ("faggot cells" - resembles bundle of sticks)
Note: if t(15;17) present, diagnose as AML even if initial blast count is < 20%

Prognostic factors

● In children, age < 10 years is favorable (Cancer 2006;106:2495)
Survival: excellent if DIC and hemorrhage are adequately controlled; excellent in adults with complete remission

Case reports

● 45 year old man with fatigue (Univ Pittsburgh Case #457)


● Combination chemotherapy required for sustained remissions (Hematology Am Soc Hematol Educ Program 2006:147)
● All trans retinoic acid (ATRA) causes neoplastic promyelocytes to rapidly differentiate into bizarre maturing neutrophils, but patients eventually relapse
● Arsenic trioxide (ATO) for ATRA-refractory patients; induces differentiation at low doses, marrow necrosis at high doses (Mod Pathol 2000;13:954)

Micro description

● Most cells are hypergranular promyelocytes (abundant cytoplasm, round / oval and frequently eccentric nuclei with occasional clefts or indentations, moderately condensed chromatin and indistinct nucleoli) with heavy red / purple cytoplasmic granulation that may obscure nuclear borders
● 90% have multiple Auer rods in some cells, which may resemble bundles of sticks
● Reniform (kidney shaped) nucleus; may have basophilic cytoplasm, < 20% myeloblasts
Post-treatment: may be difficult to differentiate residual disease (promyelocytes not in any particular location) from regenerating marrow (promyelocytes are perivascular and endosteal)

Micro images

Bone marrow smears (Wright-Giemsa):

Abundant azurophilic granules; left image has 2 microgranular promyelocytes with basophilic cytoplasm and lobulated nuclei

Numerous Auer rods in bundles

Bone marrow biopsy:
Bone marrow is almost completely replaced   Promyelocytes are relatively uniform with abundant
by promyelocytes with abundant cytoplasm,  cytoplasm containing dense azurophilic granules and
oval / round nuclei that are often eccentrically multiple Auer rods, nuclei are round, oval and lobulated
located, with occasional indentations/clefts,
somewhat condensed chromatin and
indistinct nucleoli

Treatment related:
Post-chemotherapy smear shows cell    Before and after arsenic trioxide
with numerous Auer rods in bundles

CD99 (figures 3C/3D)        H&E and CD99 (fig A1/A2)

Other sites:

Various images

Positive stains

● CD9, CD11a and CD11b (post-ATRA: Arch Pathol Lab Med 2003;127:e4 or arsenic trioxide: Mod Pathol 2000;13:954)
● Bright and heterogenous espression (flow cytometry): CD2 (23%), CD13, CD33, CD64 (27%), CD79a (86% but varies by clone, Am J Clin Pathol 2007;128:306), myeloperoxidase (strong) and HLA-DR (9%)
● Variable CD34, CD71 and CD99

Negative stains

● CD11b (but post-treatment is positive), CD11c (Am J Clin Pathol 1998;109:211), CD14, CD36, CD41, CD61 and glycophorin A

Molecular description

● t(15;17) translocation not found in other AML subtypes (Atlas of Genetics and Cytogenetics)
● Breakpoints at PML gene on #15q22 and retinoic acid receptor alpha (RARα) gene on #17q21
● Hybrid mRNA produces abnormal retinoic acid receptor that blocks myeloid differentiation
● Cases without Auer rods usually have additional chromosomal abnormalities besides t(15;17) (Am J Clin Pathol 1999;112:113)

Table 3: cytogenetic abnormalities in APL (eMedicine):

Translocation    Genes Involved    All-Trans-Retinoic Acid Response
t(15;17)(q21;q11) PML/RARα      Yes
t(11;17)(q23;q11) PLZF/RARα      No
t(11;17)(q13;q11) NuMA/RARα    Yes
t(5;17)(q31;q11)   NPM/RARα     Yes
t(17;17)     stat5b/RARα    Unknown

Molecular images

t(15;17) - arrowheads at breakpoints  Karyotype
on abnormal chromosomes

FISH - negative and positive control of t(15;17)

Electron microscopy description

● Auer rods have tubular substructure, markedly dilated endoplasmic reticulum and stellate complexes of rough ER
● Nucleus has dispersed chromatin and prominent nucleolus

Electron microscopy images

Cytoplasm has numerous dense granules and   Cross section of Auer rod shows characteristic tubular structure
several Auer rods, nucleus has dispersed
chromatin and prominent nucleolus

End of Leukemia - Acute > Recurrent genetic abnormalities > Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARα

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