Diagnosis and Treatment of Patients With Acute Myeloid Leukemia With Myelodysplasia-Related Changes (AML-MRC)

Daniel A. Arber, MD; Harry P. Erba, MD, PhD


Am J Clin Pathol. 2020;154(6):731-741. 

In This Article

Identification and Diagnosis of AML-MRC

Diagnostic Criteria for AML-MRC

The prognostic significance of dysplastic changes in the nonblast cells of patients with AML was first described by Gahn et al[9] in 1996. In 2002, the World Health Organization (WHO) introduced the category of "AML with multilineage dysplasia," which applied to patients who had 20% or more blasts in the blood or bone marrow and dysplasia in 50% or more of cells in two or more hematopoietic cell lineages.[10] In 2008, the WHO expanded the category to include patients with a history of MDS or MDS/MPN and those with certain myelodysplasia-related cytogenetic abnormalities, thus creating the AML-MRC category.[11]

According to the 2016 WHO Classification Table 1, the current AML-MRC designation applies to patients with AML who have 20% or more blasts in the blood or bone marrow and who meet any of the following criteria: a history of MDS or MDS/MPN, such as chronic myelomonocytic leukemia (CMML); an MDS-related cytogenetic abnormality; or multilineage dysplasia in 50% or more of two or more cell lineages (ie, dysgranulopoiesis, dyserythropoiesis, or dysmegakaryopoiesis; Image 1) in the absence of NPM1 or biallelic CEBPA mutations (if the diagnosis is based on multilineage dysplasia alone).[1] AML-MRC includes a variety of cytogenetic abnormalities, including complex karyotypes (defined as three or more unrelated abnormalities, not including core binding factor rearrangements and the PML/RARA rearrangement) and other specified unbalanced and balanced abnormalities[1] (Table 1). Dysgranulopoiesis includes hypogranularity, nuclear hyposegmentation of granulocytes (ie, Pelger-Huët–like anomaly), abnormal granularity (pseudo–Chédiak-Higashi granules), and abnormally segmented nuclei.[3,4] Dyserythropoiesis includes megaloblastosis, nuclear budding, irregular nuclear contours, nuclear fragmentation, multinucleation, karyorrhexis, nuclear bridging, ring sideroblasts, and cytoplasmic vacuolization.[3,4] Dysmegakaryopoiesis includes small size, nuclear hypolobation, nuclear hypersegmentation, and separated nuclear lobes.[3,4]

Image 1.

Morphologic features of multilineage dysplasia. A, Dysplastic changes are usually most prominent on the bone marrow aspirate or peripheral blood smear. In this case, erythroid precursors show irregular nuclear contours (white arrow), granulocytes demonstrate clumped nuclear chromatin without complete segmentation and hypogranular cytoplasm (black arrows), and a small, hypolobated megakaryocyte is present (white arrowhead). Some blast cells are small (black arrowheads) and may be mistaken for lymphocytes (Wright-Giemsa, ×600). B, The bone marrow biopsy specimen is hypercellular with a heterogenous cellular composition. Dysplastic small and large megakaryocytes, with detached nuclear lobes, are easily identified on the biopsy specimen (some marked with arrows) (H&E, ×400).

The AML-MRC diagnosis excludes cases of therapy-related AML and AML with cytogenetic abnormalities qualifying for a diagnosis of AML with recurrent genetic abnormalities, such as t(8;21), inv(3), and t(6;9), the latter two of which may have multilineage dysplasia.[1,12] Although not part of the disease definition, various gene mutations are more commonly associated with AML-MRC, including mutations of ASXL1, TP53, and U2AF1, and may have prognostic significance within this group.[13–15]

The patient's clinical history, cytogenetic analysis, mutational analysis, and morphologic evaluation are all important for the diagnosis and prognosis of AML-MRC, as well as for informing treatment decisions. Since there are now newer initial treatment options for this subset of patients, it is critical for the pathologist to offer the diagnosis of AML-MRC as soon as possible, which may require amending reports after receipt of cytogenetic and molecular genetic results. Patients with a known history of MDS or MDS/MPN are the easiest to diagnose, as they can be diagnosed based on clinical history. However, diagnosis on the basis of karyotype requires a longer period of time to complete the necessary assessments. Assessment of multilineage dysplasia requires a skilled hematopathologist comfortable with evaluation of dysplastic features, as well as adequate aspirate samples to judge morphologic changes and sufficient residual hematopoietic precursors to confidently comment on dysplastic features in 50% or more of the cells. If AML-MRC is diagnosed based on only multilineage dysplasia, then mutational analysis is also required to exclude patients with NPM1 and biallelic CEBPA mutations, and this information is typically not immediately available. Some,[16] but not all,[17,18] early studies suggested that multilineage dysplasia alone was not predictive of a worse prognosis in patients with intermediate-risk cytogenetics who lacked a history of MDS or MDS/MPN. However, subsequent studies have shown this is only the case in the presence of NPM1 and CEBPA mutations. AML cases with these mutations may have multilineage dysplasia, which is not prognostically significant. In the absence of such mutations, however, multilineage dysplasia remains a predictor of poor prognosis[19] and a criterion for the diagnosis of AML-MRC.[1]

The pathologist must integrate all of this information into the final report as quickly as possible to allow the clinician to make timely treatment decisions. Because an accurate diagnosis of AML-MRC requires critical clinical information, as well as integration of morphology, cytogenetics, and, at times, molecular genetic studies, such a diagnosis creates reporting challenges. Timing of the analyses to accurately diagnose patients with AML-MRC also represents a significant challenge to the optimal treatment of patients. Such challenges in the reporting of AML specimens have been summarized in more detail elsewhere,[20–22] but all reports need to record information related to prior MDS or MDS/MPN and morphologic descriptions with quantification of dysplasia in nonblast cells, when present. Subsequent cytogenetic and molecular genetic findings must be integrated into a final report to ensure an accurate diagnosis. Ultimately, changes in the diagnostic and therapeutic pathways may be needed to provide optimal treatment of patients with AML-MRC.

Assessments Necessary for AML-MRC Diagnosis

The 2017 guidelines from the College of American Pathologists and the American Society of Hematology specify that the following assessments and testing methods should be employed to accurately identify different subtypes of AML, including AML-MRC.[20] These assessments can help to differentiate AML-MRC from other subtypes of AML Figure 1.

Figure 1.

Simplified diagnostic algorithm for AML-MRC.1,3 AML, acute myeloid leukemia; AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm.

A thorough patient history and relevant clinical data, including a physical examination, imaging findings, and blood laboratory values, should be obtained.[20] Patient medical history is important for identifying and excluding individuals with therapy-related AML.[3] According to the current WHO classification, patients with a history of prior cytotoxic therapy should be diagnosed as having therapy-related AML even if they also have features of AML-MRC (eg, antecedent therapy-related MDS that develops into AML).[1]

Metaphase cytogenetic analysis, fluorescent in situ hybridization (FISH) testing, and/or reverse transcriptase–polymerase chain reaction (RT-PCR) should be performed to identify cytogenetic abnormalities and differentiate AML-MRC from the WHO classification category of AML with recurrent cytogenetic abnormalities. FISH analysis (as opposed to metaphase karyotype) of de novo AML may be able to more rapidly identify patients with AML-MRC based on MDS-related cytogenetic abnormalities. AML FISH panels typically include probes for −5, del(5q), −7, and del(7q), which may aid in identifying patients with AML-MRC. Furthermore, probes for other translocations could identify deletions on other chromosomes; if three or more abnormalities are detected, a diagnosis of AML-MRC could be considered. Finally, FISH panels will exclude t(8;21), inv(16), and t(15;17), which are excluded from AML-MRC regardless of the complexity of the karyotype.[1] However, it should be noted that the WHO classification is based on karyotype and not FISH findings, and the significance of an abnormal FISH result in the setting of a normal karyotype with 20 metaphases remains to be determined. A study from the University of Pennsylvania compared results of rapid FISH testing (MDS panel; turnaround time of <6 hours) with those of metaphase chromosome analysis in 31 adults thought to potentially have therapy-related AML or AML-MRC. Fifteen (48%) patients were identified as having MDS-related cytogenetics by metaphase chromosome analysis; of these, 12 (80%) patients were also identified by rapid FISH analysis and one additional patient was known to have a history of MDS, demonstrating the feasibility of rapid FISH analysis in combination with clinical history for identifying patients with AML-MRC.[23] While one could argue that rapid FISH testing is not necessary when an adequate karyotype is available, such testing may allow patients to receive specialized therapy for AML-MRC earlier, which might justify the added expense. Furthermore, the karyotypic analysis may fail due to lack of metaphases; the FISH analysis could provide valuable clinical information in this setting as well.

A fresh bone marrow aspirate smear in conjunction with a bone marrow trephine core biopsy specimen, bone marrow trephine touch preparations, and/or marrow clots should undergo morphologic evaluation by a hematopathologist. There are a few specific situations in which bone marrow may have some of the features of AML-MRC but cannot be classified as such. For example, AML not otherwise specified (AML-NOS) categories, including acute megakaryoblastic leukemia, may have dyspoiesis in one cell line but cannot be considered AML-MRC based on the presence of unilineage dysplasia alone. Cases of pure erythroid leukemia and cases previously diagnosed as acute erythroleukemia (erythroid/myeloid type) may have myelodysplasia-related cytogenetic abnormalities and dyspoiesis in multiple cell lines, but these cases do not have 20% or more myeloblasts.[1,3,20] Cases meeting prior criteria of the erythroid/myeloid type of erythroleukemia are now classified as MDS.[1,24]

Finally, mutational analysis should minimally be performed for FLT3, NPM1, CEBPA, RUNX1, IDH1, and IDH2 based on various guidance;[1,20,25,26] although these mutational analyses are currently insufficient for a diagnosis of AML-MRC by themselves, additional mutational analyses can be useful for estimating prognosis and informing treatment decisions. While TP53 mutations are commonly associated with a complex karyotype in AML and therefore a diagnosis of either AML-MRC or therapy-related AML,[13] such testing is not included in most guidelines since other features are present in these cases to determine the diagnosis. Immunohistochemical analysis of p53 shows an increase in some patients with AML-MRC,[27] but this is generally related to a complex karyotype and other features of AML-MRC and is not usually needed for diagnosis.