Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Recurrent genetic abnormalities
APL with PML-RARA


Topic Completed: 1 February 2013

Minor changes: 22 June 2020

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PubMed Search: Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12)


Syed Zaidi, M.D.
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Cite this page: Zaidi S. APL with PML-RARA. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/leukemiaAPL.html. Accessed August 6th, 2020.
Definition / general
  • 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
APL microgranular variant
  • Formerly called AML-M3v
  • Note: "variant" APL without further description may mean microgranular variant or an APL variant other than t(15;17)
  • Peripheral blood white blood count usually elevated, in contrast to hypergranular form
  • Diagnosis: cytogenetics recommended because other AML cases may appear similar (Am J Clin Pathol 2002;117:651)
APL with t(V;17)(V;q12)
  • Note: "variant" APL without further description may mean microgranular (morphologic) variant or cytogenetic variant other than t(15;17)
  • Uncommon, involves retinoic acid receptor alpha on #17 but not PML gene on #1
  • t(11;17) is most common; also called ZBTB16-RARα variant
  • Symptoms: disseminated intravascular coagulation / DIC common (Atlas of Genetics and Cytogenetics: t(11;17)(q23;q21) ZBTB16/RARA [Accessed 2 April 2018])
  • May NOT respond to all-trans retinoic acid therapy; may be more aggressive than classic APL (Blood 1995;85:1083)
  • Recommended to combine cytogenetics, FISH and molecular biology to document presence / absence of PML-RARα fusion gene in complex cases (Cancer Genet Cytogenet 2005;159:69)
Case reports
Treatment
  • 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)
Microscopic (histologic) 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)
  • Microgranular variant: predominatly bilobed leukemic cells have fewer and smaller cytoplasmic granules, usually multiple Auer rods but less than classic (hypergranular) promyelocytic leukemia; nuclei is folded, convoluted and markedly irregul
  • APL with t(V;17)(V;q12): Features are intermediate between hypergranular acute promyelocytic leukemia (M3) and acute leukemia with maturation (M2), most cells have many granules and regular nuclei; usually no Auer rods but increased pseudo Pelger-Huet cells
Microscopic (histologic) images

Bone marrow smears (Wright-Giemsa):
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Abundant azurophilic granules;
2 microgranular promyelocytes
with basophilic cytoplasm
and lobulated nuclei



Bone marrow biopsy:
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Bone marrow is almost completely replaced by promyelocytes
with abundant cytoplasm, oval / round nuclei that are often
eccentrically located, with occasional indentations / clefts,
somewhat condensed chromatin and indistinct nucleoli

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Promyelocytes are relatively uniform
with abundant cytoplasm containing dense
azurophilic granules and multiple Auer
rods, nuclei are round, oval and lobulated



Treatment related:
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Post-chemotherapy smear
shows cell with numerous
Auer rods in bundles



Microgranular variant:
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Promyelocytes have abundant fine
azurophilic cytoplasm with variable
size and basophilia, markedly
lobulated and invaginated nuclei

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Small hyperbasophilic promyelocytes
with prominent cytoplasmic budding,
most cells have sparsely granular
cytoplasm and lobulated nuclei


Images hosted on other servers:

Bone marrow smears (Wright-Giemsa):
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Abundant azurophilic granules



Stains:
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CD99 (figures 3C/3D)

Positive stains
Negative stains
Molecular / cytogenetics description

Table 3: cytogenetic abnormalities in APL (eMedicine: Acute Myeloid Leukemia (AML) Workup [Accessed 2 April, 2018]):

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 / cytogenetics images
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t(15;17) - arrowheads at breakpoints
on abnormal chromosomes


Images hosted on other servers:
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t(11;17)(q23;q21) variant

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
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Cytoplasm has numerous dense
granules and several Auer rods,
nucleus has dispersed chromatin
and prominent nucleolus

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Cross section of Auer
rod shows characteristic
tubular structure


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Microgranular variant: smaller granules than hypergranular
variant, granules are more
uniform in size and endoplasmic
reticulum is prominent

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Small granules
and stellate array
of endoplasmic
reticulum

Differential diagnosis
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