Indian Pediatrics 2001; 38: 72-76
Syndromes in Childhood and Adolescence:
Myelodysplastic syndromes (MDS) are clonal hemopoietic disorders characterized by ineffective hemopoiesis and a high propensity to transform into acute leukemia. MDS are now being increasingly recognized in children(1-6) and account for 1 to 5.5% of all pediatric hematological malignancies(2,3). There is a paucity of data on childhood MDS from our country(2). The present study describes the clinico-hematological features of MDS in children and adolescents diagnosed at our center. The interesting clinical features and the diagnostic difficulties encountered are highlighted.
A total of 90 patients were diagnosed as primary MDS over 16 years (Jan 1980-Dec 1995) at the Department of Hematology AIIMS, New Delhi. Twenty-four (26.6%) of these patients were below 18 years of age. Case records of these patients were retros-pectively analyzed. None of these patients had received prior chemotherapy or been exposed to toxins. Adequate trials with hematinics ruled out nutritional deficiency states. Other causes for refractory cytopenia as G-6PD defi- ciency, paroxysmal nocturnal hemoglobinuria, immune hemolysis and hemoglobinopathies had been excluded by specific laboratory tests. The diagnosis of MDS was based on morphological analysis of Giemsa stained peripheral blood and bone marrow smears as per the recommendation of the FAB Cooperative Group(6). Prussian blue staining for iron was done in each case. Bone biopsies were studied wherever available. Cytogenetic studies were not performed in any of these cases.
There were 23 males and one female patient in the age range 2-18 (mean 9.1) years. There were eight patients of refractory anemia (RA), 12 of refractory anemia with excess blasts (RAEB), three of refractory anemia with excess blasts in transformation (RAEB-t) and one of juvenile chronic myelomonocytic leu-kemia (JCMML). The duration of symptoms prior to presentation at our hospital ranged from 0.5 to 16 (mean 8.3) months. Pallor, fever and bleeding manifestations were present in 95.8% (n = 23), 45.8% (n = 11) and 33.3% (n = 8) patients, respectively. One case had only mucosal bleeding and isolated thrombo-cytopenia at presentation. Hepato megaly and/or splenomegaly (³3 cm) was seen in seven (29%) patients, and two had splenomegaly more than 10 cm in size. Proptosis at presentation was seen in 2 patients and generalized lymphadenopathy was observed in three patients. None of the patients had skeletal abnormalities or other congenital malformations.
Hemoglobin (Hb) ranged from 2.0-10.5 g/dl; total leukocyte count (TLC) from 1.2-36 ´ 103/ml; and platelet count from 13-160 ´ 103/ml. Eight patients had a TLC ³10 ´103/ml (RA 1, RAEB 4, RAEB-t 2, and JCMML 1). The distribution of patients in relation to the degree of anemia, leukopenia and thrombocytopenia in the different sub-types of MDS is shown in Table I. The bone marrow was hypocellular in two cases and normo to hypercellular in the rest. Abnormal localization of immature precursors (ALIP) in the peri-sinusoidal central region of the marrow spaces was identified in four cases (RAEB 2, RAEB-t 2). Ringed sideroblasts (>15%) were present only in one case which had 6% BM blasts (RAEB). BM biopsy was evaluated in 12 cases. None of the biopsies showed marrow fibrosis.
Patient Management and Follow Up
The patients were managed with supportive care. Blood transfusions were given when Hb dropped below 6 g/dl. Platelet transfusions were given to control bleeding episodes.Three patients developed tuberculosis after the initial diagnosis and were treated with anti-tuberculous drugs. Two patients each received anabolic steriods, danazol and prednisolone. One patient had received ALG during the initial hypoplastic phase. No significant improvement was observed in any of the patients and most remained transfusion dependent. None of the patients received chemotherapy, retinoic acid analogues or growth factors.
Fourteen out of 24 patients had a follow up for 4 weeks or more (range: 1 month-15 months). Worsening of peripheral blood counts, increased requirement for blood trans-fusion and development of sternal tenderness were taken as indicators to repeat a bone marrow examination. A repeat bone marrow was done in 9/14 cases. In 4 of them transformation to a higher sub-type/acute leukemia was documented (Table I). The average duration for transformation was 6 months. These cases demonstrate the disease progression from RA through RAEB, RAEB-t to AML and recapitulate the process of leukemogenesis.
MDS constituted 6% of all hematological malignancies in childhood in this tudy, similar to figures quoted from another center in India(2) and higher than the figure of 1-3% of pediatric hematological malignancies reported elsewhere(3). Many interesting clinical and laboratory features were noted in this study. While it is observed that childhood MDS is usually of the more aggressive types(3), a significant proportion (33.3%) of our patients initially belonged to the RA sub-group. Similar observations have been made by others(2).
Hepato-splenomegaly (³3 cm) was a prominent clinical feature noted in one third of the patients. Three of these developed tuberculosis. In India, concurrent infections particularly tuberculosis, malaria, typhoid, etc., which exert an immunological load, may lead to this organomegaly and may predict a worse otucome(2,3).
Proptosis at presentation is rare in MDS and is usually seen in cases of JCMML. Acute transformation may occur at sites of extramedullary disease and precede such a change in the BM(5). Of the 2 patients who presented with proptosis, 1 progressed from RA to AML over 7 months.
It has been suggested that in a sub-group of children, MDS may be the hematological expression of a larger embryological defect(3,6). Such patients may not show progression to acute leukemia(6). This has led some workers to suggest that the FAB system is unable to classify many cases of pediatric MDS and modified classification systems are required to better define the disease(6,7). No congenital malformations were observed in any of our patients. Moreover, certain sub-types of MDS in childhood like infantile monosomy 7 syndrome show overlaping features as leukocytosis, monocytosis and splenomegaly, with myeloproliferative dis-orders like juvenile CML. Spontaneous in-vitro growth of BM-progenitors, striking hypersensitivity to GM-CSF, lack of the peculiar cytogenetic abnormality and Hb F levels may differentiate JCML from the former(8). In the absence of cytogenetics infantile monosomy could not be diagnosed in this series.
According to the International Prognostic Scoring System (IPSS) the nature of cytogenetic abnormality, percentage of bone marrow blasts and the number of lineages involved in cytopenias are the most important variables for disease outcome in MDS(9). Although due to unequal number of cases, no comparisons can be made among the sub-types of MDS, it is noteworthy that the number of and degree of cytopenias in the higher sub-types was proportionately more (Table I). Contrary to the usual leukopenia, leucocytosis was observed in 33.3% of patients. Two of these had developed tuberculosis. Inter-current infections may result in a reactive leucocytosis. Variable leucocyte counts(2) and leukemoid reactions(10) have been reported in MDS and may result from an increased sensitivity of the clonal stem cells to growth factors(1). Leukocytosis creates diagnostic difficulties and application of scoring systems based on degree of cytopenias can be erroneous.
Hypomegakaryopoiesis was noted in 8 cases. In 6 out of these cases, bone marrow biopsy showed dysplastic micromegakaryo-cytes in 3 and reduced number in another 3. BM biopsy is more informative than aspirates in such cases.
The treatment regimens for MDS are continuously evolving. While supportive therapy is still the mainstay of management, restoration of normal hemopoiesis is the ultimate goal. The results of potential differntiating agents as retinoids and vitamin D analogues and of treatment with chemo-therapeutic regimens have been disappoint-ing(11,12). Hemopoietic growth factors are highly effective in supporting neutrophil (G-CSF and GM-CSF) and red cell production (erythropoietin) thus ameliorating cytopenias. However, the high cost of growth factors prevents their routine use in our country. None of our patients could afford growth factor therapy. Bone marrow transplantation (BMT) is the primary curative therapy for MDS and has shown very encouraging results in young patients with a low disease burden and favorable cytogenetics(11,12). Nonavailabi-lity of HLA matched donors, regimen related toxicity, recurrent infections and the high cost are major obstacles. To the best of our knowledge, BMT for MDS is still not being performed in India.
Finally, a precise diagnosis and prognostic categorization are central to establishing a treatment plan in MDS. Molecular and cytogenetic studies will lead to better understanding of the disease in children and development of individualized treatment protocols.
Contributors: ZNS was involved in the collection and analysis of laboratory data, drafting of the manuscript and will act as guarantor for the paper. RK contributed in collection and analysis of the clinical data and in drafing the manuscript. HPP was involved in the intial design of the study and analysis of data. VPC contributed towards the intellectual content, clinical data, and critical comments.