Pediatric Myelodysplastic Syndromes (MDS) Pathology

Updated: Dec 17, 2019
  • Author: David Head, MD; Chief Editor: Christine G Roth, MD  more...
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Myelodysplastic syndrome (MDS) is a set of disorders characterized by marrow failure with peripheral blood cytopenias, a peculiar set of morphologic abnormalities in hematopoietic cells, increased marrow blasts in some cases, frequent characteristic cytogenetic abnormalities, and frequent progression to a subset of acute myeloid leukemia (AML). [1, 2, 3]  The incidence of MDS increases exponentially with increasing age; the median age is estimated to be in the 70s. [2, 4, 5] The image below depicts typical morphologic features that may be seen in MDS.

Pediatric myelodysplastic syndromes pathology. A = Pediatric myelodysplastic syndromes pathology. A = binucleate megaloblastoid erythroid precursor; B = megaloblastoid erythroid precursor; C = small megakaryocyte with monolobate nucleus.

Adult MDS includes both low-grade, slowly progressive or nonprogressive subtypes (eg, MDS with single lineage or unilineage dysplasia [MDS-UD] [formerly refractory cytopenia with unilineage dysplasia (RCUD)], MDS with ringed sideroblasts [MDS-RS] [formerly refractory anemia with ringed sideroblasts (RARS)], and 5q- syndrome), as well as high-grade, potentially progressive, and life-threatening subtypes (eg, MDS with multilineage dysplasia [MDS-MD] [formerly refractory cytopenia with multilineage dysplasia (RCMD)] and MDS with excess blasts [MDS-EB] [formerly refractory anemia with excess blasts (RAEB)]). [1, 2]

AML with background MDS (AML with myelodysplasia-related changes [AML-MRC]) is difficult to treat, being resistant to cytotoxic chemotherapy, whereas background myelodysplastic hematopoiesis is abnormally sensitive to chemotherapy. If patients with AML-MRC respond to chemotherapy, they typically revert to clonal hematopoiesis (MDS) rather than a complete remission. AML-MRC may be preceded by overt MDS or may simply exhibit the cytogenetic changes and hematopoietic dysplasia typical of MDS. At present, AML-MRC, like MDS, is curable only with an allogeneic stem cell transplant.

MDS and AML-MRC are less common in children and young adults than in older adults and elderly persons. Nevertheless, a significant subset of pediatric myeloid disease (estimated at 10%-15%) consists of MDS and AML-MRC. [6, 7, 8, 9] The low-grade nonprogressive subtypes of MDS found in older patients (especially 5q- syndrome and MDS-RS) are rare to nonexistent in pediatric patients.

Diagnosis and correct subclassification of MDS-related entities are often difficult, but because both their treatment and their prognoses differ substantially from those of the more common de novo AML [eg, AML with t(15;17), t(8;21), inv(16), or t(9;11)], recognition of MDS and AML-MRC is critical for treatment, prognostication, and analysis of biologic and clinical studies. Although these entities typically occur with no antecedent causative event, there is a known set of precipitating causes, which include alkylating agents, platinum derivatives, nitrosoureas, ionizing radiation, and benzene derivatives.

Disorders included in MDS-related diseases of childhood are:

  • MDS (refractory cytopenia of childhood [RCC], MDS-EB)


  • Therapy-related MDS and AML

Given the excellent outcome of MDS and AML in Down syndrome patients with chemotherapy, their apparent single gene (GATA-1) founder mutation, and their differing morphology from other MDS disease, they should now be considered a separate entity distinct from MDS. See also Pathology of Myeloid Proliferations Related to Down Syndrome.

This discussion does not address juvenile myelomonocytic leukemia, a related disorder with mixed features of MDS and a myeloproliferative neoplasm.

See also the following:



Myelodysplastic syndrome (MDS) accounts for 10%-15% of pediatric myeloid disease, after excluding patients with Down syndrome and juvenile myelomonocytic leukemia. Precise incidence figures have proven difficult to ascertain, in part because of diagnostic difficulties and a lack of awareness of diagnostic possibilities in general pediatric medical practice. Best estimates of the incidence of pediatric MDS are in the range of 2 cases/million/year; in comparison, the estimate for acute myeloid leukemia (AML) is 6 cases/million/year, and that of acute lymphoblastic leukemia (ALL) is 40/million/year. [6, 7, 8, 9]

In contrast with MDS in adults and especially elderly persons, MDS in childhood shows no sex predilection. Especially in pediatric patients, some MDS cases are related to underlying constitutional syndromes, including Fanconi anemia, Shwachman-Diamond syndrome, Kostmann syndrome, familial thrombocytopenia with mutation of AML1, and dyskeratosis congenita, as well as following severe aplastic anemia.

Still other cases of MDS are related to therapy, occurring after treatment with cytotoxic agents that cause cross-link DNA damage (alkylating agents, platinum derivatives, nitrosoureas) or after treatment with ionizing radiation.


Clinical Features

Myelodysplastic syndrome (MDS) is a marrow failure disorder of unexplained etiology, characterized typically by clonal hematopoiesis, dysplastic morphology in hematopoietic precursors, peripheral cytopenias, a set of characteristic cytogenetic abnormalities, sometimes increased myeloid blasts in marrow or peripheral blood, and normocellular to hypercellular marrow.

The predominant presenting features of MDS relate to cytopenias (ie, anemia, neutropenia, and thrombocytopenia). [1, 2] These features may be symptoms (eg, fatigue, infection, petechiae, bleeding), or they may be abnormalities identified incidentally during the evaluation of another process.

MDS-related disease may be recognized initially by its presentation as acute myeloid leukemia (AML), with morphology demonstrating hematopoietic dysplasia or with cytogenetic changes typical of MDS (eg, -7, +8, 20q-, acquired +21). Therapy-related disease may present with unexplained cytopenias, delayed recovery of counts after chemotherapy, dysplastic morphologic features or increased blasts in the blood or marrow, or MDS-type cytogenetic abnormalities.

Patients with an associated constitutional syndrome typically (but not invariably) display the features of that syndrome (eg, skeletal abnormalities in Fanconi anemia or dystrophic nails in dyskeratosis congenita) in addition to features of MDS. Diagnosis of complicating MDS must be based on features that are not directly attributable to the underlying syndrome. For example, features of marrow failure cannot be used as corroborative evidence of MDS in a disease setting that already includes marrow failure, such as Fanconi anemia.


Morphologic Features

The dysplastic morphologic features of pediatric myelodysplastic syndrome (MDS) are identical to those of adult disease (see the images below), with one important exception [1, 2] : ringed sideroblasts are rare in pediatric MDS. If ringed sideroblasts are seen in children, the diagnosis of Pearson syndrome should be considered. [10] The marrow is typically normocellular to hypercellular, but hypocellular MDS is more common in pediatric than in adult patients. None of these features is specific for MDS, nor are they completely sensitive for a diagnosis of MDS. Similar morphologic abnormalities are seen in megaloblastic processes, and individual features are seen in a variety of other disease processes.

Pediatric myelodysplastic syndromes pathology. A = Pediatric myelodysplastic syndromes pathology. A = binucleate megaloblastoid erythroid precursor; B = megaloblastoid erythroid precursor; C = small megakaryocyte with monolobate nucleus.
Pediatric myelodysplastic syndromes pathology. A = Pediatric myelodysplastic syndromes pathology. A = multinucleate erythroid precursor; B = binucleate megaloblastoid erythroid precursor; C = dysplastic erythroid nuclei.
Pediatric myelodysplastic syndromes pathology. A = Pediatric myelodysplastic syndromes pathology. A = vacuolated erythroblasts; B = hypogranular band.
Pediatric myelodysplastic syndromes pathology. Int Pediatric myelodysplastic syndromes pathology. Internuclear bridge between erythroid precursors (arrow).
Pediatric myelodysplastic syndromes pathology. Hyp Pediatric myelodysplastic syndromes pathology. Hypogranular Pelger-Huet neutrophils and dimorphic hypochromic and normochromic red blood cells.
Pediatric myelodysplastic syndromes pathology. Mic Pediatric myelodysplastic syndromes pathology. Micromegakaryocytes with single or multiple, small, round nuclei.

Common erythroid abnormalities in pediatric MDS are as follows:

  • Blood: Bimodal red blood cell (RBC) distribution, anisocytosis and poikilocytosis (A&P), basophilic stippling, siderocytes, dysplastic features in circulating precursors

  • Marrow: Cloverleaf nuclei, megaloblastoid change, multinucleation, vacuolization, periodic acid-Schiff (PAS) positivity, and internuclear bridging (INB); although INB is characteristic of congenital dyserythropoietic anemia (CDA)-1, it is also seen occasionally in MDS and, given the rarity of CDA-1, INB is seen considerably more frequently in MDS; as noted earlier, the ringed sideroblasts seen frequently in adult MDS are not seen in pediatric MDS

Common myeloid abnormalities are as follows:

  • Blood: Pelger-Huet anomaly, hypogranulation, hypersegmentation, blasts

  • Marrow: Increased blasts, nucleocytoplasmic asynchrony (immature/blastic nucleus in a cell with differentiating cytoplasm), hypogranulation, myeloperoxidase deficiency, abnormal localization of immature precursors (ALIP) (location of immature myeloid precursors away from boney trabeculae in biopsy sections). Blasts are usually myeloid but may have megakaryoblastic or erythroid differentiation, or may be present in mixed populations. The blast percentage in both blood and marrow should be quantified in Wright-Giemsa stained smears, not by flow cytometry or immunohistochemistry on tissue sections.

Common platelet-megakaryocytic abnormalities include the following:

  • Blood: Large, agranular, or vacuolated platelets

  • Marrow: Small mononuclear megakaryocytes; large megakaryocytes with multiple small nuclei, intermediate-sized megakaryocytes with monolobate nuclei, or large megakaryocytes with hyperchromatic nuclei

Some patients with MDS have mild-to-moderate marrow fibrosis, compromising preparation of air-dried, Romanowsky-stained smears. Most morphologic features in marrow in MDS are difficult to assess with hematoxylin and eosin (H&E)–stained sections. Wright-Giemsa–stained touch preps may be very useful in this setting and should be prepared with every biopsy. Reticulin staining is helpful to verify and quantify fibrosis.


Immunophenotypic Features and Methods

There are no specific immunophenotypic features of myelodysplastic syndrome (MDS) with current routine clinical flow cytometry. However, flow cytometry of marrow is useful to separate hematogones (early B precursors, which may spuriously raise the total blast percentage) from myeloid blasts. Flow is also useful for characterization of blasts and for evaluation of T/NK-cell subsets (to rule out large granular lymphocyte [LGL] syndrome, which may mimic some features of MDS). Of note, the blast percentage in blood and marrow should be quantitated by Wright-Giemsa morphology in smears, not by flow cytometry.

With an expanded antibody panel, flow cytometry may demonstrate abnormal differentiation patterns or aberrant antigen expression in myeloid, monocytic, and erythroid elements. [11, 12, 13, 14, 15] Identification of such abnormalities involves use of a larger panel of differentiation antigens than current clinical practice, and it requires a level of expertise in both performance and interpretation for recognition of abnormalities. Although such usage is not yet widespread, this testing is anticipated to become an important adjunct to diagnosis of MDS.

Immunohistochemistry has limited applicability to the diagnosis of MDS. Myeloperoxidase (MPO) or CD117 staining may help demonstrate abnormal localization of immature precursors (ALIPs). CD34 and CD117 may help quantify blasts in difficult cases, but the actual blast percentage should be based on Wright-Giemsa–stained smears. CD41/CD61 are useful for identification of small megakaryocytes and megakaryoblasts. Glycophorin A and E-cadherin are useful for identifying erythroid precursors, and together with MPO and CD41/CD61, are useful for assessing hematopoiesis in tissue sections.


Molecular/Genetic Features and Methods

Karyotypic analysis of marrow is essential for evaluation of myelodysplastic syndrome (MDS). A large set of cytogenetic abnormalities are found with varying frequency in MDS, most consisting of gain or loss of large segments of chromosomal material. The most common abnormalities in children are -7/7q-, +8, 20q-, and acquired +21. One of the most common abnormalities in adult MDS, 5q-/-5, is virtually absent in pediatric MDS. [2, 16, 17] The molecular biologic correlates of these various cytogenetic abnormalities remain unknown.

A small set of recurring translocations are uncommonly found in MDS. These include inv3(q21q26), t(3;3)(q21;q26), t(1;7), t(2;11), t(11;16), t(3;21), and other 3q abnormalities; some associated molecular abnormalities have been identified. [1, 2, 18, 19] Translocations involving 3q26 upregulate EVI-1, a competitive inhibitor of GATA-1; GATA-1 is required for differentiation of erythroid and megakaryocytic precursors. Translocations at 11q23 disrupt MLL (HRX), a transcription factor that regulates maturation of hematopoietic progenitors. Translocations at 21q22 disrupt AML1 (RUNX1,CBFa2), a transcription factor that regulates maturation of hematopoietic progenitors.

Most importantly, the common balanced translocations typical of pediatric and young adult AML [t(15;17), t(8;21), inv(16) or t(16;16), t(9;11), t(11;17), t(11;19), t(8;16)] are not found in MDS-related disease. [20]

Fluorescence in situ hybridization (FISH) analysis for the common abnormalities of MDS is not helpful at diagnosis, as significant abnormalities are observed in the karyotype. If abnormalities are observed in the karyotype, FISH may be added for specific abnormalities to establish a baseline, as FISH may be helpful for follow-up to quantify residual disease. Screening for Fanconi anemia with a diepoxybutane (DEB) challenge is recommended, and molecular testing for the genetic abnormalities of specific syndromes (eg, dyskeratosis congenita, Shwachman-Diamond syndrome, and Fanconi anemia) may be considered. In addition, a major update to the revised 2016 World Health Organization (WHO) classification is the addition of the category of myeloid neoplasms with germline predisposition; these patients may present with MDS, myeloproliferative neoplasm (MPN), or acute leukemias. [3] The specific underlying genetic abnormality should be noted as part of the diagnosis. [3]


Diagnosis and Classification

Parameters routinely used to diagnose myelodysplastic syndrome (MDS) are peripheral blood cytopenias, dysplasia, genetic/cytogenetic abnormalities, and blasts in peripheral blood or increased blasts in marrow. [7]

Diagnosis is frequently problematic in that none of these parameters is completely sensitive or specific for this purpose. Peripheral blood cytopenias have myriad causes, as do peripheral blood and marrow dysplasia. Cytogenetic abnormalities similar to those of MDS may appear transiently in other settings, including megaloblastic processes, aplastic anemia, and Fanconi anemia. Monosomy 7 unrelated to any of these settings may be present transiently, regressing spontaneously or with treatment (eg, folate or vitamin B-12 replacement). At least in patients with therapy-related MDS—and presumably, by extension, in other MDS patients—any of these parameters may be lacking, including dysplastic morphology and cytopenias.

Because of these limitations, better methods of diagnosis are needed, but until such methods become available, at least two of the four cited parameters (unexplained cytopenias, multilineage dysplasia, cytogenetic abnormalities, and increased blasts) should be present to provide some certainty of the diagnosis of MDS. [7]

Parameters used for diagnosis should be unrelated to any underlying preexisting condition (eg, cytopenias in aplastic anemia or Fanconi anemia). A careful analysis to rule out other possible causes of abnormalities is always warranted. As a rule, definitive diagnosis should be deferred until abnormalities are shown to be sustained over several months.

Pediatric MDS comprises a more limited set of diseases than MDS in older patients. [2, 7, 17] In older patients, multiple subtypes of MDS are categorized into two broad groups: (1) low-grade disease with little tendency to progress to higher-grade disease (MDS or acute myeloid leukemia [AML]) and (2) high-grade disease with a strong tendency to progress. Low-grade MDS in older patients includes MDS with unilineage dysplasia (MDS-UD), MDS with ringed sideroblasts (MDS-RS), and 5q- syndrome. High-grade MDS in older patients includes MDS with multilineage dysplasia (MDS-MD), MDS with excess blasts (MDS-EB) (subgroups -1 and -2), and therapy-related MDS.

The low-grade MDS subtypes of adults are rare in pediatric patients, and the clinical utility of separating adult MDS-EB into subgroups on the basis of blast percentages has not been established for pediatric disease. Thus, in practice, only three MDS categories are used in pediatric patients: Refractory cytopenia of childhood (RCC, corresponding approximately to MDS-MD in adults), MDS-EB, and therapy-related MDS.

Criteria for these three subtypes are essentially the same as for the corresponding conditions in adults. RCC should have unexplained cytopenias (anemia, neutropenia, and/or thrombocytopenia), with no increase in blasts in marrow and only rare blasts in peripheral blood. MDS-EB is similar but with increased blasts in marrow or blood. Therapy-related MDS requires a history of appropriate chemotherapy or ionizing radiation.

Both RCC and RAEB in childhood may follow prolonged courses with little progression of cytopenias or blast percentage over months (RAEB) to years (RCC); therefore, a period of follow-up with repeat marrow examination may be prudent before undertaking aggressive treatment such as stem cell transplantation in these patients. Similarly, patients diagnosed as AML with myelodysplasia-related changes (AML-MRC) with a relatively low blast percentage (20%-30%) may have a relatively indolent course, similar to RAEB; as with RAEB, a period of follow-up may be helpful to define the patient's disease course.

Myelodysplastic syndrome with excess blasts vs MDS-related AML

Distinguishing between MDS-EB and MDS-related AML (AML-MRC) is often problematic and, as noted in the previous paragraph, may be more semantic than biological. [2] This distinction has been based on the progression of blasts beyond a threshold of 20% (historically 30%) of marrow elements, but this approach is simplistic. The intent of a diagnosis of AML is to inform the clinician that the patient has a proliferative disease that may respond to aggressive cytotoxic chemotherapy. However, blasts per se do not prove proliferation, only a lack of differentiation. Blastic chromatin indicates DNA dissociation from histones. For example, blastic chromatin is found in cells with nucleocytoplasmic asynchrony, in which nuclei look blastic but cytoplasmic maturation disproves a significant mitotic rate. Knockout of an appropriate histone deacetylase also results in blastic dissociated chromatin without proliferation.

As noted previously, patients with blasts in the 20%-30% range or even higher may have a clinical picture of marrow failure (MDS) rather than progressive tumor burden (AML). Either situation is potentially life threatening, but optimal treatment may differ. Marrow failure patients tend to respond poorly to cytotoxic chemotherapy, which is also virtually never curative. In contrast, proliferating blasts in this setting may respond to chemotherapy, albeit with prolonged cytopenias in many cases because of the sensitivity of background hematopoiesis (MDS); if the chemotherapy is effective, patients typically revert to clonal hematopoiesis (MDS) rather than normal hematopoiesis.

Which pattern of disease a given patient will follow (ie, predominant marrow failure or proliferation) cannot usually be discerned with a single marrow examination. If possible, definitive diagnosis should be delayed for several weeks, with a repeat marrow examination to clarify the patient's course. In patients with a high blast percentage at presentation, a diagnosis of AML-MRC is justified.

Therapy-related MDS/AML versus other therapy-related leukemia syndromes

In the appropriate clinical setting (history of alkylating agent, platinum derivative, or ionizing radiation exposure), diagnosis of therapy-related MDS is based on the presence of prolonged cytopenias after chemotherapy or the onset of cytopenias unrelated to chemotherapy, the appearance of MDS-related cytogenetic abnormalities, dysplastic changes in hematopoietic cells, and/or increased myeloid blasts. [2] If the blast count exceeds 20%, diagnosis of therapy-related AML is warranted. Patients initially may have only a single feature (eg, monosomy 7 in a marrow sample or unexpectedly prolonged cytopenias after chemotherapy). Dysplastic morphology or increased blasts may be lacking.

Distinction should be made between therapy-related MDS/AML and two other therapy-related leukemia syndromes. Epipodophyllotoxin chemotherapy causes translocations involving the MLL gene at 11q23 and, to a lesser extent, the AML1 gene at 21q22. [21] Therapy-related leukemia with an MLL translocation includes acute lymphoid leukemia (ALL) and AML. Complex therapy including all of the above noted agents plus other chemotherapy (eg, anthracyclines) also causes an increased incidence of AML, with each of the balanced translocations found in AML [eg, t(15;17), t(8;21) or inv(16)]; although the incidence of this complication is not as high as those of the previous two syndromes, it is several logs higher than that in the general population. [22] Neither of these latter two syndromes is related to MDS.


Differential Diagnosis

Accurate diagnosis of myelodysplastic syndrome (MDS) is imperative, given the progressive course of disease, the drastic intervention (stem cell transplantation) needed for curative treatment, and the possible serious consequences of other diseases in the MDS differential.

The differential diagnosis of MDS is extensive. Major considerations in childhood are constitutional syndromes (Kostmann syndrome, Shwachman-Diamond syndrome, Fanconi anemia, dyskeratosis congenita, congenital dyserythropoietic anemias, Pearson syndrome and other congenital sideroblastic processes, constitutional megaloblastic anemias, familial thrombocytopenia with AML1 mutation, rare others).

Other major considerations include chronic viral infection (Epstein-Barr virus [EBV], human immunodeficiency virus [HIV], parvovirus B-19, cytomegalovirus [CMV]), folate deficiency, copper deficiency, aplastic anemia, and de novo acute myeloid leukemia (AML) with a recurring balanced translocation [eg, t(8;21)] but a low marrow blast percentage.

Recognition of many of these entities requires only appropriate testing: antibody titers, vitamin and copper levels, and cytogenetic analysis. As discussed earlier, the presence of ringed sideroblasts should suggest a cause other than MDS.

Constitutional syndromes versus MDS

Distinguishing MDS from some of the cited constitutional syndromes may be particularly problematic. These syndromes not only mimic MDS clinically and morphologically, but also may progress to MDS and AML (eg, Kostmann syndrome, Shwachman-Diamond syndrome, Fanconi anemia, dyskeratosis congenita, familial thrombocytopenia).

Diagnosis of each syndrome is beyond the scope of this article. However, some patients do not present until later in life (eg, patients with mild Fanconi anemia and dyskeratosis congenita) and may be first recognized at the time of progression to MDS or AML. Recognition of the progression of a syndrome to MDS should be based on appearance of at least two of the four abnormalities stated previously (unexplained cytopenias, dysplasia, clonal cytogenetic abnormalities, increased blasts) that are not directly attributable to the underlying syndrome. [7]

Again, it is important to note that unsustained clonal cytogenetic abnormalities unrelated to progression to MDS have been reported in some of these entities.

Aplastic anemia versus hypocellular MDS

Distinguishing aplastic anemia from hypocellular MDS may be difficult. As many as 15% of cases of severe aplastic anemia progress over time to MDS or AML, typically a late complication in long-term survivors.

The interrelationship of MDS and aplastic anemia is poorly understood. Some low-grade cases of MDS respond to immunosuppression, like aplastic anemia, and both aplastic anemia and MDS may have a paroxysmal nocturnal hemoglobinuria (PNH) clone, another interrelationship that is poorly understood. Aplastic anemia may have transient clonal cytogenetic abnormalities similar to those of MDS; if sustained, they suggest progression to MDS. Aplastic anemia generally lacks significant dysplastic morphology, although minor dysplastic changes may be present. The presence of sustained increased blasts suggests progression to MDS.


Prognosis and Predictive Factors

Although some cases of pediatric myelodysplastic syndrome (MDS) may follow a stable or slowly progressive course, the long-term prognosis is generally poor, whether due to cytopenias or progression to AML. The International Prognostic Scoring System (IPSS) for MDS has not proven useful in pediatric MDS. [7, 23, 24, 25]  Some evidence suggests that the rate of disease progression in pediatric disease may vary with specific cytogenetic abnormalities. [26] The most frequent abnormalities, monosomy 7 and complex abnormalities, follow an aggressive course with poor survival without treatment. Patients with trisomy 8 are infrequent, but some data suggest they may experience slower progression of disease. [26] Some patients may benefit from immunosuppression, similar to aplastic anemia.

Nevertheless, the only current curative option is allogeneic stem cell transplantation. [27] Aggressive cytotoxic chemotherapy is virtually never curative in this setting and may induce prolonged, life-threatening cytopenias. Alternative approaches, such as demethylating agents (azacytidine, decitabine) and the thalidomide analogue lenalidomide, are not curative, the side effects of long-term treatment (which must be determined before use in a child) are unknown, and extended therapy may be prohibitively expensive. [28]

Even allogeneic stem cell transplantation, with its attendant treatment-related morbidity and mortality, has a high relapse rate. If MDS progresses to acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), the leukemia tends to be resistant to chemotherapy; primary drug resistance, prolonged therapy-related cytopenias, and short clonal remissions are seen. As with MDS, the only curative treatment is allogeneic stem cell transplantation.


Myeloid Diseases in Down Syndrome

Transient abnormal myelopoiesis

As many as 10% of children with Down syndrome experience a leukemoid reaction in the neonatal period. This reaction is referred to as transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder. [3, 29, 30]  TAM may also occur in phenotypically and cytogenetically normal children with so-called mosaic Down syndrome, usually corresponding to +21 confined to a hematopoietic clone with normal constitutional cytogenetics.

TAM is characterized by a leukemoid peripheral blood picture with leukocytosis, multilineage immature precursors with dysplastic features, and variable numbers of blasts. The number of circulating blasts may suggest a diagnosis of acute myeloid leukemia (AML) if the overall clinicopathologic setting is not recognized. The patient may be anemic or thrombocytopenic.

Marrow examination shows similar features, with multilineage dysplasia; blasts may be less prominent than in peripheral blood. Blasts often have morphologic and immunophenotypic features of megakaryoblasts: basophilic cytoplasm, surface blebs, binucleation or multinucleation, a tendency to clustering, and positivity for CD41/CD61 by flow or immunohistochemical analysis.

The course of TAM is self-limited, resolving to normal hematopoiesis over 1 to several months. Nevertheless, if the leukemoid reaction or the cytopenias are marked, they may cause life-threatening complications that necessitate intervention. In addition to +21, the abnormal clone in TAM has a loss-of-function mutation of GATA-1, and about one third of patients with TAM develop myelodysplastic syndrome (MDS) and AML over the ensuing 3 years, with features of acute megakaryoblastic leukemia, background dysplasia, and the same GATA-1 mutation as with TAM. [31, 32]

MDS and AML in Down syndrome

The incidence of MDS and AML in Down syndrome before age 3 years is 1%-2%, 3-4 logs greater than that in nonaffected children. [33] The AML has MDS-related features. Patients may follow a progressive course through MDS to AML, although the pre-AML stages are not always documented.

Whereas MDS and AML in Down syndrome are combined as a single entity in the current World Health Organization (WHO) classification of hematopoietic malignancies, as they have similar behavior that is not dependent on the blast count. [3, 34] The morphologic features of each stage are similar to those of disease in non-Down syndrome children and adults, with notable exceptions. Dysplastic features are restricted to erythroid and megakaryocytic lineages, with little to no myeloid dysplasia. Megakaryocytic dysplasia is unique, with a frequent large central eosinophilic inclusion and peripherally displaced nuclei, often forming a ring resembling a Touton giant cell. See the images below.

Pediatric myelodysplastic syndromes pathology. Bon Pediatric myelodysplastic syndromes pathology. Bone marrow section, hematoxylin and eosin. Note the megakaryocytes (arrows) with a peripheral ring of nuclei (resembling Touton giant cells) and central eosinophilic inclusions displacing the nuclei.
Pediatric myelodysplastic syndromes pathology. Bon Pediatric myelodysplastic syndromes pathology. Bone marrow aspirate, Wright-Giemsa stain. Note the megakaryocyte with a central mass displacing the nuclei peripherally.

The blasts usually have megakaryoblastic features, although erythroblastic or mixed differentiation is also seen. The common myeloid or monocytic differentiation of AML in other settings is not seen in Down syndrome. Possibly in connection with the megakaryoblastic features, patients often have mild-to-modest marrow reticulin fibrosis, impeding aspiration of a good marrow sample for evaluation.

In addition to +21, the abnormal clone usually has a GATA-1 loss-of-function mutation, and if there was preceding TAM, the GATA-1 mutation is identical. [31, 32]  GATA-1 is necessary for normal maturation of erythroids and megakaryocytes. This may explain the predominance of megakaryoblastic and erythroid differentiation of blasts in both TAM and MDS/AML of Down syndrome, and limitation of dysplasia to the same lineages.

Although the relationship of TAM to subsequent MDS and AML remains conjectural, a plausible explanation is that the loss-of-function GATA-1 mutation in TAM prevents maturation of a clone of cells being driven to proliferate by a physiologic cytokine storm in the neonatal period. As the cytokines recede over time, the attendant TAM resolves. The patient retains the GATA-1 mutation in a hematopoietic stem cell and is at later risk to progress to AML if a genetic drive to proliferate is acquired by subsequent mutation in the GATA-1 clone. Presence of the GATA-1 mutation in both TAM and subsequent MDS/AML suggests that it is the founder mutation of the disease process.

Notably, both MDS and AML before age 3 years in patients with Down syndrome respond favorably to chemotherapy, uniquely among MDS-related diseases, and better than AML in the general pediatric population. Treatment is equally effective whether provided at the stage of MDS or after progression to AML, and patients may be treated before progression to overt AML. Given this excellent outcome, the presence of an apparent single gene founder mutation (GATA-1) and unique morphology versus other MDS-related disease, Down syndrome appears to be a specific entity that should be distinguished and separated from the rest of MDS-related diseases.


Additional Resources

For more information of myelodysplastic syndromes (MDS), consult the following references:

  • Hasserjian RP, Head DR. Myelodysplastic syndromes. In: Jaffe ES, Arber DA, Campo E, Harris NL, Quintanilla-Fend L eds. Hematopathology. 2nd ed. Philadelphia, Pa: Elsevier; 2016.

  • Head DR, Thompson MA. Diagnosis and classification of the acute myeloid leukemias. In: Estey EH, Faderl SH, Kantarjian HM, eds. Hematologic Malignancies: Acute Leukemias. Berlin, Germany: Springer; 2008:21-46. (Includes discussion of the role of the MDS in acute myeloid leukemia [AML] pathogenesis.)