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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.

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

Treatment
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● 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
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● 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
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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

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

Other sites:

Various images

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

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


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

Electron microscopy description
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● 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
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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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