Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Recurrent genetic abnormalities

AML with mutated NPM1



Minor changes: 20 October 2021

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: NPM1 mutated AML[TIAB]

Mark Russell, M.D.
Kamran M. Mirza, M.D., Ph.D.
Page views in 2020: 143
Page views in 2021 to date: 258
Cite this page: Russel M, Mirza KM. AML with mutated NPM1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticAMLmutatedNPM1.html. Accessed December 3rd, 2021.
Definition / general
  • Acute myeloid leukemia (AML) with mutations in the NPM1 gene, a common recurrent genetic abnormality found in a subset of patients with AML
Essential features
  • One of the most common recurrent genetic abnormalities in AML
  • Associated with better prognosis
  • Associated with monocytic and myelomonocytic morphology
  • NPM1 immunohistochemistry showing cytoplasmic localization may be used as a surrogate for PCR
Terminology
  • Acute myeloid leukemia with cytoplasmic nucleophosmin
ICD coding
  • ICD-11: 2A60.0 - acute myeloid leukemia with recurrent genetic abnormalities
Epidemiology
  • Typically presents de novo in adults
  • F > M
Sites
  • Bone marrow
  • Extramedullary involvement may occur
    • Most common sites are gingiva, lymph nodes and skin
Pathophysiology
  • Exon 12 mutation leading to aberrant localization of nucleophosmin and nucleophosmin associated proteins in the cytoplasm; while not completely understood, this may cause several hypothetical leukemogenic events (Leukemia 2017;31:798)
    • NPM1 mutation causes HOX gene upregulation which supports the leukemic state in NPM1 mutant AML (Cancer Cell 2018;34:499)
Etiology
  • Unknown at this time
Clinical features
  • NPM1 mutations are one of the most common recurrent genetic lesions in AML
    • Occurs in approximately 35% of AML cases overall and 50 - 60% of cases with normal karyotype (Blood Rev 2018;32:167
  • Patients often present with anemia and thrombocytopenia, although platelet counts are usually higher than other AML subtypes (Blood 2005;106:3740
Diagnosis
  • Requisite blast percentage for a diagnosis of AML is ≥ 20% myeloblasts, monoblasts / promonocytes or megakaryoblasts in the peripheral blood or bone marrow
  • NPM1 mutation
    • Detection via molecular techniques
    • Aberrant cytoplasmic expression detected via immunohistochemistry
Prognostic factors
  • AML with mutated NPM1, normal karyotype and absence of FLT3 internal tandem duplication mutation has characteristically favorable prognosis
    • In younger patients, the prognosis is similar to AML with t(8;21) or AML with inv(16)
  • NPM1 and FLT3 tyrosine kinase domain paired mutations offer higher overall and event free survival (Blood 2008;111:2527)
  • Myeloid immunophenotype is associated with poorer relapse free survival and overall survival and is associated with more CD34 expression (Blood Adv 2019;3:3322)
Case reports
Treatment
  • Most patients receive conventional induction and consolidation chemotherapy with cytarabine and an anthracycline
  • Patients do not receive allogeneic stem cell transplant
  • Possible role of all trans retinoic acid (ATRA) as an adjuvant to induction therapy
    • ATRA and arsenic work synergistically to degrade cytoplasmic NPM1, inducing apoptosis, growth arrest and differentiation
      • Also shown to sensitize NPM1 mutant leukemic cells to daunorubicin
  • Addition of gemtuzumab ozogamicin (GO), a CD33 antigen targeting immunoconjugate, has shown an increase in the likelihood of NPM1 mutation negative minimal residual disease (Leukemia 2017;31:798)
Microscopic (histologic) description
  • Wide range of morphologies are seen in AML with NPM1 mutation (N Engl J Med 2005;352:254)
  • There is a strong association between both acute myelomonocytic and acute monocytic leukemia and NPM1 mutation (Blood 2007;109:874)
  • NPM1 mutations are also detected in AML with and without maturation and in pure erythroid leukemia
  • Cup-like nuclei are highly associated with the presence of NPM1 and FLT3 internal tandem duplication mutations (Cancer 2009;115:5481)
Microscopic (histologic) images

Contributed by Kamran M. Mirza, M.D., Ph.D.
Blasts with cup-like indentations Blasts with cup-like indentations

Blasts with cup-like indentations

Positive stains
Negative stains
  • CD34 is negative in most cases
Flow cytometry description
Molecular / cytogenetics description
  • 4 base pair insertion in exon 12 of NPM1; detected via reverse transcription PCR
Sample pathology report
  • Bone marrow, left posterior iliac crest, bone marrow core biopsy, aspirate, clot and peripheral blood:
    • Acute myeloid leukemia with mutated NPM1
    • Pancytopenia with rare circulating blasts (see comment)
    • Comment: Peripheral smear shows pancytopenia with macrocytic anemia and mild anisopoikilocytosis with microcytes, macrocytes and occasional elliptocytes. Rare circulating blasts are present.
    • The bone marrow core biopsy is of sufficient length for evaluation. There are multiple patchy hypercellular areas showing shows increased numbers of blasts in clusters with markedly decreased maturing / mature myeloid forms. Few scattered megakaryocytes with normal morphology are apparent. Erythropoiesis is decreased, although maturing precursors are still present in clusters.
    • The aspirate smear shows that many of the blasts have a folded nuclei with often bilobed nuclei with prominent nucleoli in a few blasts reminiscent of cup-like nuclear invaginations in a proportion of blasts (8 - 9%) and moderate amount of gray-blue cytoplasm. Auer rods are not present. A differential count yields 83% blasts. Few residual erythroid precursors and occasional megakaryocytes are present without significant dysplasia in either of these 2 cell lines. Very few residual maturing myeloid forms are present. Iron stain shows decreased sideroblastic iron and adequate storage iron. Cytochemistry stains (alpha naphthyl butyrate esterase and myeloperoxidase) are performed and show the following: the blasts are myeloperoxidase positive (5 - 10% of blasts) and alpha naphthyl butyrate (monocyte) esterase is negative in all the blasts.
    • Flow cytometry analysis shows an abnormal myeloid blast population expressing dim CD45, dim CD56 (subset), dim CD38, CD34, dim CD33, CD117 and dim CD13. The blasts are negative for HLA-DR.
    • NPM1 mutation analysis confirms the presence of NPM1 mutation
Differential diagnosis
Board review style question #1
A 50 year old woman presented with generalized gingival swelling, pain and bleeding. The patient's initial laboratory workup showed leukocytosis, anemia and thrombocytosis. A bone marrow biopsy is performed which showed increased blasts with cup-like morphology and cytoplasmic NPM1 staining. Which of the following is true about this entity?

  1. Blasts are frequently CD34 positive
  2. It has poor prognosis
  3. It is most frequently associated with normal karyotypes
  4. It is rare
Board review style answer #1
C. AML with mutated NPM1 frequently has normal karyotypes.

Comment Here

Reference: AML with mutated NPM1
Board review style question #2
Which of the following histologic features is acute myeloid leukemia with mutated NPM1 most associated with?

  1. Coin on coin nuclear morphology
  2. Dwarf megakaryocytes
  3. Immature eosinophils with large, violet granules
  4. Monocytic and myelomonocytic morphology
Board review style answer #2
D. Monocytic and myelomonocytic morphology is commonly associated with NPM1 mutation.

Comment Here

Reference: AML with mutated NPM1
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