Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Other AML entities defined by the WHO
AML therapy related


Minor changes: 10 July 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Therapy related myeloid neoplasms [title]

Valentina Sangiorgio, M.D.
Marie Calaminici, M.D., Ph.D.
Page views in 2020 to date: 60
Cite this page: Sangiorgio V, Calaminici M. AML therapy related. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/bonemarrowneoplastictherapy.html. Accessed August 13th, 2020.
Definition / general
  • Therapy related myeloid neoplasm refers to cases of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myelodysplastic / myeloproliferative neoplasms (MDS / MPN) occurring as a late complication of cytotoxic chemotherapy or radiation therapy
  • Established cases of MPN, MDS or MDS / MPN progressing into AML should not be regarded as therapy related but rather as secondary AML
Essential features
  • Occurs as a late complication of cytotoxic therapy or radiation therapy administered for neoplastic and nonneoplastic conditions
  • Can either present with a chronic phase characterized by progressive bone marrow failure (i.e. t-MDS or t-MDS / MPN) or present as overt leukemic phase (i.e. t-AML)
  • Most common etiologies are alkylating agents, topoisomerase II inhibitors and ionizing radiation therapy; other agents are less commonly implicated
  • Is diagnosed and classified using analogous criteria to the corresponding de novo diseases
  • Prognosis is generally poor, compared to the corresponding de novo malignancies
Terminology
  • Therapy related myelodysplastic syndrome (t-MDS); therapy related myelodysplastic / myeloproliferative neoplasm (t-MDS / MPN); therapy related acute myeloid leukemia, alkylating agent related; therapy related acute myeloid leukemia (t-AML)
ICD coding
  • ICD-O: 9920/3 - Therapy related myeloid neoplasm
Epidemiology
Pathophysiology
  • t-MDS, t-MDS / MPN and t-AML occur as the consequence of acquired somatic alterations induced by cytotoxic or radiation therapy
  • Alterations occur within hematopoietic stem cells and progenitor cells and confer a proliferative or survival advantage
  • Alkylation produces inaccurate base pairing during replication and breaks in the DNA double helix as the alkylated bases are repaired (Mutat Res 1996;355:41)
  • Topoisomerase II inhibitors cause chromosomal breakages which favor the development of chromosomal translocations (Chem Res Toxicol 1993;6:585)
  • As only a minority of patients treated eventually develop a therapy related myeloid neoplasm, other factors may contribute to the pathogenesis
  • Mutations in DNA damage sensing or repair genes (as BRCA1/2 or TP53) or polymorphisms in genes affecting drug metabolism or DNA repair mechanisms are the most common secondary events (Proc Natl Acad Sci U S A 2001;98:11592, Cancer 2016;122:304, Leukemia 2007;21:1413, JAMA 2011;305:1568)
Etiology
  • t-MDS, t-MDS / MPN and t-AML develop mostly following the exposure to (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017):
    • Alkylating agents: melphalan, cyclophosphamide, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, dacarbazine, procarbazine, carmustine, mitomycin C, thiotepa, lomustine
    • Topoisomerase II inhibitors: etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, actinomycin
    • Large field ionizing radiation therapy
    • Antimetabolites: thiopurines, mycophenolate mofetil, fludarabine
    • Antitubulin agents (often in combination with other agents): vincristine, vinblastine, paclitaxel, docetaxel
  • Other agents (hydroxyurea, radioisotopes, L-asparaginase, purine analogues, mycophenolate mofetil) possibly involved but their primary role is unknown
Clinical features
  • Majority of t-MDS, t-MDS / MPN and t-AML develop within 10 years after the initial exposure
  • Cases related to alkylating agents:
    • Represent the majority of cases
    • Occur 5 - 10 years after initial exposure
    • Are characterized by a chronic phase of bone marrow failure and progressive cytopenia(s) which correspond to a t-MDS
  • Cases related to topoisomerase II inhibitors:
    • Represent a minority of the cases
    • Occur after a short latent period (< 5 years)
    • Present as overt t-AML, without a preceding chronic phase
  • If latency period over 10 years, the hematological malignancy may not be related to therapy (J Clin Oncol 2015;33:3641)
  • Signs and symptoms are related to the presence and severity of cytopenia(s) (i.e. anemia, thrombocytopenia, leukopenia)
Diagnosis
  • Complete blood count with differentials and morphologic review of blood smears to assess for cytopenia(s), dysplasia and blast count
  • Bone marrow aspirate and biopsy with features of either MDS, MDS / MPN or AML
  • Cytogenetic tests (i.e. conventional karyotyping, FISH) and molecular analysis (i.e. next generation sequencing) for diagnosis, clinical management and risk stratification
  • Reference: Foucar: Diagnostic Pathology - Blood and Bone Marrow, 2nd Edition, 2017
Laboratory
  • Complete blood counts with differentials:
    • Variable cytopenia(s) following exposure to alkylating agents
    • Leukocytosis more common after exposure to topoisomerase II inhibitors
  • Additional tests to exclude other underlying causes of cytopenia(s), as clinically appropriate (i.e. vitamin B12, folate and iron, Coombs test, etc.)
  • Reference: Foucar: Diagnostic Pathology - Blood and Bone Marrow, 2nd Edition, 2017
Prognostic factors
  • Advanced age, poor performance status and low hemoglobin are unfavorable prognostic factors (Am J Hematol 2015;90:E80)
  • Cytogenetic findings are key prognostic factors (Blood 1995;86:3542)
    • Abnormalities on chromosome 5 or 7, TP53 mutation or loss and complex karyotype predict poor prognosis with median survival time < 1 year from diagnosis
    • Balanced translocations including t(15;17), inv(16) or t(16;16) generally harbor better prognosis
    • Therapy related t(15;17), inv(16) or t(16;16) have shorter median survival compared with their de novo counterparts
Case reports
Treatment
Microscopic (histologic) description
  • t-MDS, t-MDS / MPN and t-AML due to alkylating agents (Foucar: Diagnostic Pathology - Blood and Bone Marrow, 2nd Edition, 2017):
    • Increased cellularity
    • Multilineage dysplasia, commonly striking
    • Increased blast count
    • Variable fibrosis
  • t-MDS, t-MDS / MPN and t-AML due to topoisomerase II inhibitors (Foucar: Diagnostic Pathology - Blood and Bone Marrow, 2nd Edition, 2017):
    • Increased cellularity
    • Frequent features of acute monoblastic, acute monocytic or acute myelomonocytic leukemia
    • Common rearrangements involving 11q23
    • Other AML with recurrent cytogenetic alterations
      • Acute promyelocytic leukemia with t(15;17)(q24.1;q21.2)
      • Acute myeloid leukemia with t(8;21)(q22;q22.1)
      • Acute myeloid leukemia with inv16(p13.1q22)
  • Myeloblasts, monoblasts and megakaryoblasts are included in the blast count
  • Promonocytes are considered blasts equivalent in the setting of acute monoblastic, acute monocytic and chronic / acute myelomonocytic leukemia
  • Blast count on bone marrow samples (alongside peripheral smears) used to drive final diagnosis (i.e. t-MDS and t-MDS / MPN: < 20%; t-AML: ≥ 20%)
  • Primary neoplasm may be manifest (i.e. plasma cell neoplasms, lymphomas): typically form discrete lesions
Microscopic (histologic) images

Contributed by Valentina Sangiorgio, M.D.

t-MDS: hypercellular bone marrow

t-MDS: bland reticulin fibrosis

t-MDS: myeloid hypoplasia with left shifting


t-AML: hypercellular bone marrow with impaired maturation

t-AML: clusters of blasts



AFIP images

Bone marrow smear

Large erythroid precursors with lobulated nuclei and karyorrhexis

PAS+ erythroid precursors in bone marrow smear

Peripheral smear description
Peripheral smear images

AFIP images

Postradiochemotherapy
and splenectomy for
Hodgkin disease

Immunohistochemistry
Flow cytometry description
  • There are no specific immunophenotypic findings in t-MDS, t-MDS / MPN and t-AML compared with the de novo counterparts
  • Blasts generally express CD34 alongside other myeloid markers (i.e. CD13, CD33, CD117, myeloperoxidase)
Flow cytometry images

Contributed by Valentina Sangiorgio, M.D.

t-AML

Molecular / cytogenetics description
  • t-MDS, t-MDS / MPN and t-AML show cytogenetic abnormalities in as many as 90% of cases
  • Around 70% of cases harbor unbalanced chromosomal aberrations:
    • Most common alterations affect chromosome 5 (i.e. -5q or -5) and 7 (i.e. -7q or -7)
    • These generally occur in the context of a complex karyotype or co-occur with mutations or loss of TP53
    • Such changes correlate with a long latent period, a preceding phase of t-MDS and exposure to alkylating agents or radiation therapy (Leukemia 2008;22:240)
  • Around 30% have balanced translocations:
    • 11q23as frequently involved
    • Others rearrangements: t(8;21)(q22;q22.1), t(15;17)(q24.1;q21.1) and inv16(p13.1q22)
    • These cases develop shortly after exposure to the etiologic agent(s) and present with overt t-AML without a preceding chronic phase
    • Common following topoisomerase II inhibitors or radiation therapy alone (J Clin Oncol 1998;16:1897)
  • A minority of cases have a normal karyotype
  • TP53 is the most commonly mutated gene, occurring in as many as 50% of cases (Haematologica 2013;98:908)
  • NPM1 and FLT3 mutations are less common in t-AML compared with de novo AML
Molecular / cytogenetics images

Contributed by Valentina Sangiorgio, M.D.

G banding karyotype of
t-AML

Videos

Role of bone marrow transplant in therapy related AML and MDS

Sample pathology report
  • Bone marrow, biopsy and aspirate (t-AML):
    • Hypercellular for age, with infiltration (around 60%) by acute myeloid leukemia and background of multilineage dysplasia (see comment)
    • Comment: In light of the current histologic findings within the bone marrow alongside the detection of a complex karyotype and of the patient's known past medical history (breast carcinoma treated with chemo and radiation therapy), the case is best classified as therapy related acute myeloid leukemia. Clinical correlation is advised.
    • Bone marrow aspirate microscopic description (t-AML): Multiparticulate sample showing hypercellular marrow for the patient's age bone marrow (cellularity around 80%). Erythropoiesis is increased and shows prominent megaloblastoid changes; dysplastic changes in the form of multinucleation and nuclear bridging are seen. Myelopoiesis is increased with complete maturation but left shifting. Majority of neutrophils shows pseudo-Pelger-Huët changes. Megakaryocytes are seen in adequate number but are overtly dysplastic, the majority being small and hypolobated. There is prominent increase in blasts which are medium in size with scant cytoplasm and open chromatin with variably prominent nucleoli. A cell count (performed on 150 cells) reveals: 39% blasts, 20% promyelocytes / myelocytes, 11% maturing granulocyte forms, 27% erythroid precursors, 1% lymphocytes, 1% plasma cells, 1% monocytes. Prussian blue iron stain shows normal storage iron; no ring sideroblasts are noted.
    • Bone marrow biopsy microscopic description (t-AML): The description of bone marrow trephine findings is similar to the aspirate sample (see above). Additional comments should be as follow: "CD34 highlights an increase in hematopoietic precursors which account for around 30% of the total nucleated cells. Aberrant expression of CD34 within the megakaryocytes is also seen (only if seen)." Reticulin stain reveals an increased network of reticulin fibers with many intersections (WHO MF1).
    • Peripheral smear microscopic description (t-AML): Pancytopenia with dysplastic neutrophils. 15% of the nucleated cells are blasts.
Differential diagnosis
  • Chemotherapy induced dysplasia and bone marrow suppression:
    • Recent rather than remote chemoradiation therapy
    • Usually resolves after chemotherapy discontinued
    • Good response to hematopoietic growth factors (i.e. erythropoietin, G-CSF)
  • Coincidental myeloid neoplasms in patients with history of chemotherapy:
    • Lacks prototypic morphologic or genetic features of t-MDS, t-MDS / MPN and t-AML (i.e. JAK2 positive MPN unrelated to previous therapy)
Board review style question #1
Which of the following blast count on blood smear, bone marrow aspirate or trephine supports a diagnosis of therapy related AML?

  1. 10% if prior treatment with alkylating agents
  2. 10% if prior treatment with topoisomerase II inhibitors
  3. 20%
  4. 30%
Board review answer #1
Board review style question #2

Is the presence of these small and hypolobated megakaryocytes expected in therapy related myeloid neoplasms?

  1. No; small and hypolobated megakaryocytes are not a common finding in therapy related myeloid neoplasms
  2. No; small and hypolobated megakaryocytes, especially if many, suggest a myeloproliferative neoplasm
  3. Yes; small and hypolobated megakaryocytes are a common manifestation of dysplasia and can be seen in therapy related myeloid neoplasms
  4. Yes; small and hypolobated megakaryocytes are required for t-MDS
Board review answer #2
C. Yes; small and hypolobated megakaryocytes are a common manifestation of dysplasia and can be seen in therapy related myeloid neoplasms

Comment Here

Reference: AML therapy related
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