APL with PML-RARA

Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Recurrent genetic abnormalities

APL with PML-RARA

Author: Syed Zaidi, M.D.

Topic Completed: 1 February 2013

Minor changes: 21 September 2020

Copyright: 2001-2021, PathologyOutlines.com, Inc.

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

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Table of Contents

Cite this page: Zaidi S. APL with PML-RARA. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/leukemiaAPL.html. Accessed March 2nd, 2021.

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

5 year old girl with Down syndrome (J Med Case Rep 2007;1:147)
23 year old man with tuberculosis (Korean J Hematol 2012;47:229)
31 year old woman with t(17;20) masking t(15;17) variant (Cancer Genet Cytogenet 2006;168:73)
66 year old man with PRKAR1A gene (Blood 2007;110:4073)
69 year old woman post-chemotherapy for breast cancer (Cancer Genet Cytogenet 2002;138:143)
Nine years after diagnosis of essential thrombocythemia (Am J Hematol 2002;71:114)

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):

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

Bone marrow biopsy:

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

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

Treatment related:

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

Microgranular variant:

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

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):

Abundant azurophilic granules

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

Microgranular variant: usually CD2 (Leukemia 1995;9:1461), CD13, CD33, CD34 (relatively more common than hypergranular variant, Haematologica 2006;91:311) and myeloperoxidase (strong)

Negative stains

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

Molecular / cytogenetics description

t(15;17) translocation not found in other AML subtypes (Atlas of Genetics and Cytogenetics: t(15;17)(q24;q21) PML/RARA [Accessed 2 April, 2018])
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)
APL with t(V;17)(V;q12): Involves RAR alpha and either PLZF / ZBTB16 (11q23), NUMA (11q13), NPM (5q31) or STAT5b genes (Leukemia 2002;16:1927)

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

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

Images hosted on other servers:

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

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

Cross section of Auer
rod shows characteristic
tubular structure

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

Small granules
and stellate array
of endoplasmic
reticulum

Differential diagnosis

t(11;17) may resemble AML with 11q23 abnormality (Cancer Genet Cytogenet 2005;159:168)