The current perspective of low-grade myelodysplastic syndrome in children

Myelodysplastic syndrome (MDS) is a term defined as a group of clonal hematopoietic stem cell disorders characterized by cytopenia, dysplasia in any one of the myeloid lineages, ineffective hematopoiesis and a varying propensity to transform into acute myeloid leukemia (AML). MDS is uncommon in children compared to the elderly, and several differences between MDS in children and adults have been identified, such as the rarity of refractory anemia with ringed sideroblasts and MDS associated with del(5q) chromosome [1]. In addition, pediatric MDS can evolve from inherited bone marrow failure syndromes (IBMFS) such as Fanconi anemia (FA).

Considering these differences, a pediatric approach to the diagnosis and management of MDS was proposed in 2003 [1] and was incorporated into the 4th edition of the World Health Organization (WHO) classification in 2008 [2]. This classification mentioned unique characteristics of pediatric MDS without increased blasts, i.e., low-grade MDS. For example, neutropenia and thrombocytopenia are more likely to be the presenting manifestation in children in contrast to adults who often present with isolated anemia [3]. Children with low-grade MDS frequently show hypocellular marrow [3]. Consequently, “refractory cytopenia of childhood (RCC)” was introduced as a provisional entity in the 2008 WHO classification [2]. It is recommended that children who meet the criteria for refractory cytopenia with multilineage dysplasia (RCMD) be considered as RCC until the prognostic significance of a multilineage dysplasia is clarified in children [2].

This review overviews the clinical, morphological and pathobiological characteristics of low-grade MDS in childhood and discusses appropriate management and treatment strategy. Current problems concerning the concept of “RCC” are also addressed.

Pediatric MDS is an uncommon disorder accounting for 5–10 % of all hematological malignancies in childhood [1]. Of those, low-grade MDS is the most common subtype. From February 2009 to October 2013, 1000 children who were suspected of having MDS, myeloproliferative neoplasms and bone marrow (BM) failure were prospectively registered into the Japanese Society of Pediatric Hematology/Oncology database and underwent the central review of morphology and histology [4]. Of those, 339 and 24 children were diagnosed with de novo low-grade MDS and refractory anemia with excess blasts (RAEB), respectively (Fig. 1). This indicated that the annual incidence of de novo MDS in Japan was 78 cases, more than 90 % of which were classified as low-grade MDS.

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A Japanese prospective registry revealed normal karyotype in 41 out of 65 children (65 %) with low-grade MDS, whereas monosomy 7 was found in only 5 (8 %) [5].

The 2008 WHO classification defines “RCC” as a childhood MDS characterized by persistent cytopenia with <5 % blasts in the BM, <2 % blasts in the peripheral blood (PB) and dysplastic changes in two or three lineages or exceeding 10 % in one single lineage [2]. BM cellularity was reduced in about half of the children with low-grade MDS [3, 5]. In children, cytopenias with decrease of BM cellularity might be caused by various underlying disorders, including AA, IBMFS and other hematological and nonhematological disorders [7]. Morphological abnormalities may also be found in these disorders. Of those, AA and IBMFS are the most common and important differential diagnoses of low-grade MDS, however, the clinical and histopathological distinction between these three disorders is challenging. Since hematopoietic cells in hypocellular low-grade MDS are often distributed in a patchy pattern (Fig. 2a), information obtained from aspiration cytology is limited [7, 8]. Therefore, BM biopsies, which mirror the topography and cellularity of the local hematopoiesis, should be performed at least twice to diagnose hypoplastic BM disorders in children [2, 7, 8]. Patchy erythropoiesis with impaired maturation, accompanied by sparsely distributed granulopoiesis, in an otherwise adipocytic BM is characteristic of hypoplastic low-grade MDS (Fig. 2b) [2, 7, 8]. Megakaryocytes are markedly decreased or absent. Immunohistochemistry is mandatory for the detection of micromegakaryocytes. A subset of children with low-grade MDS shows normo- or hypercellular BM, in which hematopoietic cells are diffusely distributed and dysplasia may be prominent (Fig. 2c, d).

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Since IBMFS, such as FA and dyskeratosis congenital (DC), show overlapping morphological features with low-grade MDS and AA, IBMFS has to be excluded by careful past medical and family history, and thorough physical examination. Several laboratory studies, such as chromosome breakage test and telomere length assay, should be considered in the differential diagnosis of hypoplastic BM disorders, because children without any phenotypic features can be diagnosed with IBMFS. In fact, Yoshimi et al. [9] reported that FA and DC were found in patients with hypo- or normocellular RCC with a prevalence of 14 and 2 %, respectively.

Intrinsic defects in hematopoietic stem cell caused by acquired cytogenetic and genetic abnormalities are thought as hallmark features of adult MDS. Recently, the molecular basis has been comprehensively addressed in a large cohort of MDS and AA in adults [10, 11]; however, molecular pathogenesis of pediatric MDS is still largely unknown except that spliceosome mutations are found to be rare in pediatric MDS [12].

Given that immunosuppressive therapy (IST) is effective in some children with low-grade MDS as well as MDS in adults or AA [13, 14, 15], a part of these disorders might share a common pathogenesis, that is, T cell-mediated inhibition of hematopoiesis. Indeed, T cell oligoclonality was identified in 40 % of RCC patients [16]. Minor paroxysmal nocturnal hemoglobinuria clones, which are thought to be a predictor of favorable response to IST, were also detected in 41 % of RCC patients [17]. These findings suggest that pathogenesis attributes to activated T cells in a subset of children with low-grade MDS.

The analysis of treatment outcome of 65 cases with low-grade MDS revealed heterogeneity in the clinical courses [5]. Approximately, a third of the patients remained stable for long periods without IST or hematopoietic stem cell transplantation (HSCT), whereas eight of 65 patients suffered from progressive disease.

Kardos et al. [3] reported that monosomy 7 significantly correlated with progression to advanced MDS. Because patients whose disease progressed before HSCT fared significantly worse, those with monosomy 7 as well as complex karyotype were encouraged to be transplanted as soon as possible. Those who suffer from transfusion dependency or severe neutropenia may also be candidates for HSCT if suitable donor is available. Because transplant-related mortality is the major cause of treatment failure in children with low-grade MDS [18], reduced-intensity conditioning (RIC) regimen is an attractive option [19, 20]; however, it remains to be established whether RIC is an appropriate regimen for children with low-grade MDS with multilineage dysplasia, hypercellularity, or unfavorable karyotype.

If children with low-grade MDS without unfavorable karyotype require therapeutic intervention but suitable donor is unavailable, IST may be an advisable option. IST consisting of antithymocyte globulin (ATG) and cyclosporine has proven to be effective in a subset of children with low-grade MDS, with response rate ranging from 30 to 70 % [5, 6, 14, 15, 21]. Some patients with chromosomal abnormalities or multilineage dysplasia were also reported to respond to IST [5, 6, 14, 15, 21]. However, patients who received IST remain at risk of clonal evolution and relapse, and the long-term failure-free survival rate was estimated as only 40–50 % [5, 21]. As reliable biomarkers that can predict response have not yet identified, candidates for IST should be selected with utmost caution.

RCC seems a morphologically distinctive entity, but its clinical relevance has been challenged. Forester et al. [22] performed retrospective analysis of children previously diagnosed with AA and found that histologic diagnosis of RCC did not predict IST failure or clonal evolution. Hama et al. also argued that morphological classification (AA, RCC and RCMD) did not correlate with IST response or clonal evolution in the retrospective analysis. Although some clinical features of RCC may overlap with AA, these results should be interpreted with cautions, since they retrospectively analyzed a cohort of patients who had been diagnosed with AA. Another controversial point in the concept of RCC is significance of multilineage dysplasia, which correlated with deterioration of cytopenia during the watchful observation period and disease progression in our analysis [5]. To select patients who would fail IST, experience clonal evolution and require HSCT at the early phase of the disease, comprehensive prospective study assessing prognostic values of clinical, morphological, histological and cytogenetic findings and predefined treatment assignment will be needed. In the future, molecular findings may also help prognostification in children with hypoplastic BM disorders [23].