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AML with recurrent genetic abnormalities

APL with PML::RARA


Editorial Board Member: Alexa J. Siddon, M.D.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Haley Amoth, M.D.
Anamarija M. Perry, M.D.

Last author update: 7 June 2023
Last staff update: 28 August 2024

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PubMed Search: Acute promyelocytic leukemia with PML::RARA

See Also: PML::RARA

Haley Amoth, M.D.
Anamarija M. Perry, M.D.
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Peripheral smear images | Positive stains | Negative stains | Flow cytometry description | Flow cytometry images | Electron microscopy images | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Amoth H, Perry AM. APL with PML::RARA. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/leukemiaapl.html. Accessed December 25th, 2024.
Definition / general
  • Acute myeloid leukemia (AML) with predominance of abnormal promyelocytes and fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene
Essential features
  • Acute myeloid leukemia with predominance of abnormal promyelocytes, characterized by t(15;17)(q24.1;q21.2) and leading to PML::RARA fusion
  • Young to middle aged adults are most commonly affected
  • 2 morphologic variants are hypergranular and microgranular
  • Early diagnosis and treatment are imperative due to the high risk of coagulopathy and disseminated intravascular coagulation (DIC)
  • Standard treatment includes all trans retinoic acid (ATRA) plus arsenic trioxide (ATO), with or without chemotherapy; excellent prognosis and high cure rates
  • Reference: Arch Pathol Lab Med 2015;139:1308
Terminology
  • Acute promyelocytic leukemia with PML::RARA fusion (World Health Organization Classification, 5th Edition)
  • Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2) / PML::RARA (2022 International Consensus Classification)
  • Formerly called AML M3 by the French American British classification
ICD coding
  • ICD-O: 9866/3 - acute promyelocytic leukemia with PML::RARA
  • ICD-11: 2A60.0 & XH1A50 - acute myeloid leukemia with recurrent genetic abnormalities & acute promyelocytic leukemia, t(15;17)(q22;q11-12)
Epidemiology
  • Relatively uncommon acute myeloid leukemia subtype
  • Young and middle aged adults are most commonly affected (20 - 59 years)
  • Accounts for 5 - 8% of acute myeloid leukemia cases in younger patients
  • Higher incidence in Latin American population (Best Pract Res Clin Haematol 2003;16:357, Cancer 2012;118:5811)
  • M ≈ F
Sites
  • Peripheral blood and bone marrow
  • Extramedullary involvement is rarely seen
Pathophysiology
  • Characterized by balanced translocation t(15;17)(q24.1;q21.2) leading to PML::RARA fusion and a PML::RARA oncoprotein
  • PML::RARA oncoprotein suppresses gene expression by recruitment of a number of transcriptional repressors, which leads to block in differentiation and malignant transformation of myeloid cells (PLoS One 2014;9:e104906)
  • Secondary chromosomal and genetic abnormalities contribute to the phenotype
Etiology
Clinical features
  • Leukopenia is a common presenting sign
  • Leukocytosis in the microgranular variant
  • Symptoms of pancytopenia are fatigue, weakness, infection, bleeding
  • High risk of coagulopathy and disseminated intravascular coagulation, especially in microgranular acute promyelocytic leukemia (Arch Pathol Lab Med 2015;139:1308, Blood Cancer J 2021;11:123)
  • Early diagnosis and treatment are imperative
Diagnosis
  • Established by detection of t(15;17) / PML::RARA fusion by RT-PCR, conventional cytogenetics or FISH
  • RT-PCR is the most sensitive method of detection, as the translocation can be cryptic by karyotype and FISH
  • Blast count can be < 20%
  • Reference: Arch Pathol Lab Med 2015;139:1308
Laboratory
  • Complete blood count showing pancytopenia
  • Leukocytosis in microgranular acute promyelocytic leukemia
  • Prolonged prothrombin time (PT) or activated partial thromboplastin clotting time (aPTT)
  • Elevated D dimer and fibrin degradation products
  • Decreased fibrinogen (Blood Cancer J 2021;11:123)
Prognostic factors
Case reports
Treatment
  • All trans retinoic acid plus arsenic trioxide is currently the standard of care for low and intermediate risk acute promyelocytic leukemia patients
  • In high risk patients, chemotherapy is added to all trans retinoic acid and arsenic trioxide
  • If arsenic trioxide is not available, combination of all trans retinoic acid and chemotherapy is used for all risk categories (Blood Cancer J 2021;11:123)
Microscopic (histologic) description
  • Bone marrow hypercellular
  • 2 cytomorphologic variants of acute promyelocytic leukemia are hypergranular (classic) and microgranular (hypogranular)
  • Hypergranular acute promyelocytic leukemia
    • Abnormal promyelocytes vary in size and shape, frequently with kidney shaped or bilobed nuclei
    • Cytoplasm packed with large granules, staining bright pink, red or purple
    • Auer rods, frequently in bundles
    • Myeloblasts with Auer rods can be seen
  • Microgranular acute promyelocytic leukemia
    • Predominantly bilobed nuclei
    • Hypogranular appearing cytoplasm due to submicroscopic size of azurophilic granules
    • Most cases have some abnormal promyelocytes with prominent granules or Auer rods (Arch Pathol Lab Med 2015;139:1308)
  • ZBTB16::RARA t(11;17) acute promyelocytic leukemia has some characteristic morphologic features (Blood 2000;96:1287)
    • More regular nucleus, not bilobed; occasionally more condensed nuclear chromatin compared with classic acute promyelocytic leukemia
    • Coarse cytoplasmic granules or less often, fine or no granules
    • No bundles of Auer rods
    • Increased number of hypogranular pelgeroid neutrophils
Microscopic (histologic) images

Contributed by Anamarija M. Perry, M.D., @sanamloghavi on Twitter and AFIP
Hypercellular bone marrow

Hypercellular bone marrow

Abnormal promyelocytes

Abnormal promyelocytes

APL with PML::RARA   APL with PML::RARA

APL with PML::RARA

APL with <i>PML::RARA</i>   APL with <i>PML::RARA</i>

APL with PML::RARA


Bone marrow biopsy   Bone marrow biopsy

Bone marrow biopsy

Bone marrow smear (Wright-Giemsa)

Bone marrow smear (Wright-Giemsa)

Treatment related

Treatment related

Microgranular variant   Microgranular variant

Microgranular variant

Peripheral smear description
  • In classic variant, pancytopenia is frequently seen with occasional circulating abnormal promyelocytes
  • In microgranular acute promyelocytic leukemia, leukocytosis with numerous abnormal promyelocytes
Peripheral smear images

Contributed by Anamarija M. Perry, M.D.
Microgranular variant

Microgranular variant

Positive stains
Negative stains
Flow cytometry description
Flow cytometry images

Contributed by Anamarija M. Perry, M.D.
Classic variant, CD13+ and CD33+

Classic variant, CD13+ and CD33+

Classic variant, HLA-DR- and CD34-

Classic variant, HLA-DR- and CD34-

Classic variant, CD34- and CD64+

Classic variant, CD34- and CD64+

Classic variant, CD34- and cyMPO+

Classic variant, CD34- and cyMPO+

Microgranular variant, moderate CD45

Microgranular variant, moderate CD45

Microgranular variant, CD2+ and CD34+

Microgranular variant, CD2+ and CD34+

Electron microscopy images

AFIP images
Missing Image

Cytoplasm and nucleus

Missing Image

Cross section of Auer rod

Missing Image

Microgranular variant

Missing Image

Small granules and stellate array

Molecular / cytogenetics description
  • t(15;17)(q24.1;q21.2) leading to PML::RARA fusion
  • PML::RARA can be detected in 90 - 95% of cases (Nature 1990;347:558)
  • 3 PML::RARA transcript isoforms (depending on the PML breakpoint location on chromosome 15): long (in intron 6, Bcr1), variant (in exon 6, Bcr2) and short (in intron 3, Bcr3) (Cancers (Basel) 2020;12:624)
  • Occasional cases have cryptic t(15;17)(q24.1;q21.2) or complex rearrangements involving an additional chromosome (Leukemia 2016;30:1672)
  • Deletion 7q and trisomy 8 are the most common frequent additional cytogenetic alterations (Cancers (Basel) 2020;12:624)
  • Variant RARA translocations (Hematol Oncol Stem Cell Ther 2020;13:189, Cancers (Basel) 2020;12:967, Arch Pathol Lab Med 2015;139:1308, Front Oncol 2022;12:871590)
    • Detected in ~5% of cases, involve RARA gene at 17q21.2 and different partners
    • Should be diagnosed as acute promyelocytic leukemia with variant RARA translocations
    • Partner genes
      • ZBTB16 at 11q23 has a poor response to all trans retinoic acid and arsenic trioxide, characteristic morphology (see Microscopic (histologic) description)
      • NUMA1 at 11q13
      • NPM1 at 5q35
      • STAT5B at 17q21 has a poor response to all trans retinoic acid and arsenic trioxide
      • PRKAR1A at 17q24
      • FIP1L1 at 4q12
      • BCOR at Xp11
      • OBFC2A at 2q32
      • TBLR1 at 3q26
      • GTF2I at 7q11
      • IRF2BP2 at 1q42
      • FNDC3B at 3q26
      • STAT3 at 17q21
      • HNRNPC at 14q11
      • NUP98
      • TNRC18
  • Most common somatic mutations include FLT3 (including FLT3 ITD and FLT3 p.D835), WT1, NRAS, KRAS, USP9X, ARID1A and EED (Leukemia 2016;30:1672, Leukemia 2019;33:1387)
Molecular / cytogenetics images

Contributed by Anamarija M. Perry, M.D. and Lina Shao, Ph.D.
Karyotype

Karyotype

FISH study

FISH study

Sample pathology report
  • Bone marrow, core biopsy, touch imprints, aspirate clot, aspirate smears and peripheral blood smears:
    • Acute promyelocytic leukemia with PML::RARA
    • Adequacy: The core biopsy represents ~7 mm of evaluable bone marrow. The aspirate materials are adequate.
    • Cellularity: Hypercellular, ~90% on average.
    • Erythroid elements: Decreased quantity. Full spectrum of maturation. No dysplasia.
    • Myeloid elements: Predominance of atypical promyelocytes in bone marrow. The neoplastic promyelocytes are large cells and most of them are heavily granulated. Many feature a lobulated nucleus and some have overlapping nuclear lobes. Rare cells with numerous (10 - 15) Auer rods are found in the bone marrow and blood smears. There is little granulocytic maturation beyond the promyelocyte stage.
    • Megakaryocytes: Adequate number. No definite dysplasia.
    • Ancillary studies: Fluorescence in situ hybridization analysis of the bone marrow aspirate is positive for PML::RARA gene fusion.
    • Complete blood count:
      • White blood cell (K/uL): 0.9
      • Red blood cell (M/uL): 3.06
      • Hemoglobin (g/dL): 10.1
      • Hematocrit (%): 27.1
      • Mean corpuscular volume (fl): 88.6
      • Red cell distribution width (%): 14.5
      • Platelet (K/uL): 106
    • Peripheral blood: Absolute leukopenia with occasional leukemic promyelocytes noted. Slight red cell anisocytosis and moderate poikilocytosis with some ovalocytes but no schistocytes. A few nucleated red cells noted on scan. Slight to moderate thrombocytopenia with some variation in platelet size and occasional hypogranular forms.
Differential diagnosis
Board review style question #1


A 27 year old woman presents with fatigue of ~2 weeks' duration and pancytopenia with marked leukopenia. Bone marrow biopsy and aspiration were performed and representative morphology is shown in the image above. Which of the following studies should be done to confirm the diagnosis suspected on morphology?

  1. FISH for MYC rearrangement
  2. FISH for PML::RARA fusion
  3. Mutation analysis for FLT3
  4. Mutation analysis for NPM1
  5. RT-PCR for BCR::ABL1
Board review style answer #1
B. FISH for PML::RARA fusion. Bone marrow aspirate shows abnormal promyelocytes. These findings are suspicious for acute promyelocytic leukemia, however, a definitive diagnosis requires detection of PML::RARA fusion, which can be done with a rapid FISH study.

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Reference: APL with PML::RARA
Board review style question #2
Which of the following immunophenotypes is characteristic for hypergranular acute promyelocytic leukemia?

  1. CD34+, CD13+, CD33+, MPO+, CD2-
  2. CD34+, CD13+, CD33+, MPO-, CD2-
  3. CD34+, HLA-DR-, CD13+, CD33+, CD64-
  4. CD34-, HLA-DR-, CD13+, CD33+, CD64+
  5. CD34-, HLA-DR+, CD13+, CD33+, CD64-
Board review style answer #2
D. CD34-, HLA-DR-, CD13+, CD33+, CD64+. Hypergranular variant of APL is characterized by low or absent expression of CD34 and HLA-DR, is usually brightly positive for CD33 and is positive for CD13 and cytoplasmic myeloperoxidase (MPO). CD64 is also frequently expressed. The other answers (A, B and C) can be eliminated since they show the phenotype of blasts that are CD34 positive or HLA-DR positive (answer E).

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Reference: APL with PML::RARA
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