Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Recurrent genetic abnormalities
APL with PML-RARA
Author: Syed Zaidi, M.D.
Last author update: 1 February 2013
Last staff update: 12 January 2023 (update in progress)
Copyright: 2001-2023, PathologyOutlines.com, Inc.
PubMed Search: Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12)
See Also: PML::RARA
Table of Contents
Definition / general | Prognostic factors | APL microgranular variant | APL with t(V;17)(V;q12) | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Electron microscopy description | Electron microscopy images | Differential diagnosisCite this page: Zaidi S. APL with PML-RARA. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/leukemiaAPL.html. Accessed January 29th, 2023.
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
AFIP images
Bone marrow biopsy
Cytology images
AFIP Images
Bone marrow smear (Wright-Giemsa)
Treatment related
Microgranular variant
Images hosted on other servers:
Abundant azurophilic granules (Wright-Giemsa)
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
AFIP 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
AFIP images
Cytoplasm and nucleus
Cross section of Auer rod
Microgranular variant
Small granules and stellate array
Differential diagnosis
- t(11;17) may resemble AML with 11q23 abnormality (Cancer Genet Cytogenet 2005;159:168)
