Pathology of Acute Myeloid Leukemia With Myelodysplasia-Related Changes

Updated: Feb 26, 2018
  • Author: Angie Duong, MD; Chief Editor: Christine G Roth, MD  more...
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Overview

Overview

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) includes those forms of AML that occur in patients with any of the following criteria:

  • A previous history of a myelodysplastic syndrome (MDS) or a myelodysplastic/myeloproliferative neoplasm (MDS/MPN)
  • An MDS-related cytogenetic abnormality
  • Multilineage dysplasia in greater than 50% of at least two cell lineages in the absence of NPM1 or biallelic CEBPA mutations.

The 2016 update to the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues has focused increased attention on genetic abnormalities to characterize and subclassify AML, including AML-MRC. [1]

AML-MRC encompasses:

  • AML arising in MDS or in MDS/MPN
  • AML with MDS-related cytogenetic abnormalities
  • AML with multilineage dysplasia

This category of AML primarily occurs in elderly patients; it is rare in children. AML-MRC represents 25%-35% of AML cases. [2, 3, 4, 5]

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Definition

By definition, the diagnosis of acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) requires the presence of at least 20% blasts in the peripheral blood (PB) and/or bone marrow (BM), an absence of any of the AML-associated recurrent genetic abnormalities seen in AML (such as inv(3), t(6;9),or  NPM1 mutation), and the absence of a history of cytotoxicity or radiation therapy for an unrelated disease. [6]

In new cases of AML, careful review of the patient's history to identify a previous diagnosis of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) and to exclude prior exposure to cytoxic treatments (chemotherapy and radiation) is necessary for proper classification.

The list of AML-MRC-related cytogenetic abnormalities is shown in the section under "Molecular/Genetic Features and Methods."

Lastly, to classify a new diagnosis of AML as having myelodysplasia-related changes based on morphology, dysplasia must be present in at least 50% of the cells in at least two bone marrow cell lines. Additionally, cases of AML with an NPM1 or biallelic CEBPA mutation are classified separately, even if sufficient morphologic evidence of dysplasia is present. [7, 8]

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Clinical and Morphologic Features

Clinical features

Patients with acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) often present with severe pancytopenia. Cases arising in association with an myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) as well as those arising in childhood may be slowly progressive.

Morphologic features

AML with multilineage dysplasia is established by demonstrating at least 20% blasts and by identifying dysplastic features in at least 50% of cells in at least two bone marrow (BM) cell lines (ie, dysgranulopoiesis, dyserythropoiesis, or dysmegakaryopoiesis). [6] Features of dysgranulopoiesis include hypogranularity, hyposegmentation of granulocytes (ie, pseudo-Pelger-Huet forms), abnormal granularity (pseudo-Chediak-Higashi granules), or abnormally segmented nuclei (see the images below). As such, cytochemical staining, especially with myeloperoxidase (MPO), may be aberrant, because patients may develop an acquired MPO deficiency as part of the dysplastic process. [9, 10, 11]

Dysplastic promyelocyte with cytoplasmic vacuole ( Dysplastic promyelocyte with cytoplasmic vacuole (left), blast (center), and dysplastic neutrophil with pseudo-Pelger-Huet anomaly and hypogranularity (right).
Dysplastic neutrophil with large pseudo-Chediak-Hi Dysplastic neutrophil with large pseudo-Chediak-Higashi granules.

Features of dyserythropoiesis include megaloblastoid forms, nuclear budding, irregular nuclear contours, nuclear fragmentation, multinucleation, karyorrhexis, mitoses within erythroid forms, ring sideroblasts, and cytoplasmic vacuolization (see the following images).

A dysplastic red blood cell with budding nuclei (l A dysplastic red blood cell with budding nuclei (left) is seen with a monocyte (center), and a blast (right).
Numerous dysplastic erythroid cells are seen inclu Numerous dysplastic erythroid cells are seen including nuclear budding, irregular nuclear contours, and multinucleation.

Features of dysmegakaryopoiesis include small size, nuclear hypolobation, nuclear hypersegmentation, and separated nuclear lobes (see the image below).

A cluster of dysplastic megakaryocytes is seen.  S A cluster of dysplastic megakaryocytes is seen. Several small and hypolobate megakaryocytes are present.

Rare cases of AML-MRC demonstrating basophilic differentiation [12] or mixed-lineage phenotype [13] have been reported.

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Immunophenotypic Features and Methods

By flow cytometry, the blasts in acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) show a myeloblast phenotype, with expression of blast markers (CD34, CD117) as well as myeloid markers such as CD13, CD33, MPO; aberrant expression of CD5, CD7, or CD56 may also be seen. The background granulocytes may also aberrantly overexpress CD33 and underexpress CD45, CD11b, and CD15 by flow cytometry. Similarly, lower expression levels of CD14, CD56, and CD45 may be seen on background monocytic populations in AML-MRC. [14]

Immunohistochemical staining of the bone marrow biopsy specimen may be especially helpful in cases with increased fibrosis and an inadequate aspirate specimen. In AML-MRC, CD34 and/or CD117 immunostains reveal numerous (>20%) blasts which often form large clusters and sheets. In cases emerging from a preexisting myelodysplastic syndrome (MDS), these stains may also highlight increased blasts located away from the bony trabeculae (atypical localization of immature precursors [ALIP]).

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Molecular/Genetic Features and Methods

The cytogenetic abnormalities that are myelodysplastic syndrome (MDS) related and are sufficient to categorize acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) (even without morphologic evidence of dysplasia) are as follows:

  • Complex karyotype: Three or more unrelated abnormalities, none of which include the recurrent cytogenetic abnormalities encountered in AML [6]

  • Unbalanced abnormalities: -7/del(7q), -5/del(5q), i(17q)/t(17p), -13/del(13q), del(11q), del(12p)/t(12p), and idic(X)(q13) [1]

  • Balanced abnormalities: t(11;16)(q23;p13.3), t(3;21)(q26.2;q21.2), t(1;3)(p36.3;q21.1), t(2;11)(p21;q23), t(5;12)(q33p13.2t(5;7)(q33q11.2), t(5;17)(q33p13.2 t(5;10)(q33q21), and t(3;5)(q25;q34) [1]

Cases of AML with NPM1 or biallelic CEBPA mutations as the only genetic alterations are classified separately, even if morphologic evidence of dysplasia is present. [1, 7, 8]

PIGN gene expression aberration appears to be associated with genomic instability and leukemic progression in AML-MRC. [15]  This gene may play an essential role in regulating mitotic integrity to maintain chromosomal stability and preventing leukemic transformation/progression.

A 2017 study indicates that when other modalities are not available, immunohistochemistry for p53 expression may be useful for identifying cases of AML-MRC that are TP53 mutated, have complex karyotype, and have poor prognosis. [16]

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Prognosis and Predictive Factors

Patients with acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) generally have a poor prognosis. The percentage of patients who achieve complete remission is lower with this form of AML than with other AML types. [17] As mentioned previously, cases arising in association with an myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) may show slower progression and thus may be less clinically aggressive. The prognosis is also affected by associated cytogenetic abnormalities. The high-risk cytogenetic abnormalities include: -5, -7, del(5q), abn(3q), and complex karyotype. [18]

The lack of prognostic significance of multilineage dysplasia in AML with mutated NPM1 or biallelic CEBPA mutations [1, 7, 8]  support the 2016 World Health Organization (WHO) updated classification of not including these entities within the spectrum of AML-MRC, even if morphologic dysplasia is present.

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