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VOL 19, NO 1 FEBRUARY 1992 3emznars in EDITOR-IN-CHIEF JohnW. Yarbro, MD, PhD ASSOCIATE EDITORS Richard S. Bornstein, MD Michael J. Mastrangelo, MD , - .. Myelodysplastic Syndromes .> .. .r Donald C. Doll, MD, an2 Alan F. List, MD, Guest Editors .:... . . , . ..,, . ., ... . ., ' , . ... . .. ..., ... ... . . . . ., . . ... . ... VOL 19, NO 1 Seminars in Oncology Myelodysplastic Syndromes FEBRUARY 1992 f Table of Contents Myelodysplastic Syndromes: Introduction..................................... Donald C. Doll and Alan F. List 1 Classification and Morphologic Features of the Myelodysplastic Syndromes....Jean E. Goasguen and John M. Bennett 4 Biology and Pathogenesis of the Myelodysplastic Syndromes..........Alan F. List and Allan Jacobs 14 i Chromosome Abnormalities in Myelodysplastic Syndromes................................... Peter C. Nowell 25 In Vitro Marrow Culture Studies in the Myelodysplastic Syndromes................ Peter L. Greenberg 34 Leukemias and MyelodysplasticSyndromes Secondary to Drug, Radiation, and Environmental Exposure.......................................................................... Ellis G. Levine and Clara D. Bloomfield 47 Chemotherapy and Bone Marrow Transplantation for Myelodysplastic Syndromes Bruce D. Cheson 85 Differentiation-Inducing Agents in the Treatment of Myelodysplastic Syndromes Masahiro Kizaki and H. Phillip Koefler 95 Treatment of MyelodysplasticSyndromes With Hemopoietic Growth Factors Peter L. Greenberg 106 Classification and Morphologic Features of the Myelodysplastic Syndromes Jean E. Goasguen and John M. Bennett PATIENTS WITH variable degrees of unexplained cytopenia(s), usually associated with a hypercellular marrow, have been classified as primary acquired myelodysplastic syndromes (MDS). In the past MDS enjoyed a diverse terminology, including "preleukemic acute leukemia,"' "smoldering acute leukemia,"* "refractory anemia,"3 "refractory anemia with excess of myeloblast^,"^ "smoldering myeloid leukemic states,"' and "dyshematopoiesis."6 Those who use the term "preleukemic" do so primarily in a restrictive sense, because theoretically all patients so described have acute leukemia and can be traced historically to have a chronic evolving bone marrow disorder that terminates in "overt" acute myeloid leukemia (AML). We now know that approximately 15% to 20% of MDS evolve to AML. The majority of these patients are older than age 50 years and have evidence of morphologic abnormalities of the myeloid lineage similar to those observed in AML, but with less than 30% blasts in the marrow aspirate. The French-American-British (FAB) Cooperative Group attempted to characterize these entities into five subgroups, based on the recognition of dysmorphic features common to all groups, and other criteria distinguishing them. Since this description' in 1976,revised in 1982' and in 1985; several cases of MDS in young patients as well as in children have been reported and will also be discussed. Dacie et al,' based on the apparent double red cell population observed on peripheral blood smears of refractory sideroblastic anemia (RAS) patients, were the first to suspect the From Universitt! de Rennes, Laboratoire d'Hematologi et d'lmmunoligie Hopital SUO, Rennes, France; and University of Rochester School ofMedicine and Dentistry, Department of Medicine and the Cancer Center, Rochester, M . Color photomicrographs were made possible by an Educational Grant to Donald C. Doll by the Burroughs Wellcome Company. Address reprint requests to Dr Jean E. Goasguen, Laboraroire d'Ht!matologie et d'lmmunologie Hopital Sud, 16 Boulevard de Bulgarie Rennes 3500, France. Copyright C 1992 by W.B.Saunders Company 0093-77541921I901-0002$05.0010 clonality of the MDS. This hypothesis was verified by studying the glucose-6-phosphatedehydrogenase (G6PD) enzyme system in patients with MDS. Furthermore, cytogeneticstudies showed involvement of multipotent stem cells in MDS patients." Using restriction fragment length polymorphisms of the X chromosome genes hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase, Janssen and associates" demonstrated that MDS arise from a multipotent hematopoietic stem cell with the potential for both myeloid and lymphoid differentiation. This finding may explain the coexistence of lymphoid or plasmacytic neoplasms with MDS reported in the literature. Because a multipotent stem cell is involved in MDS, abnormalities of all lineages may occur. The diagnosis of MDS is based on dyspoiesis of trilineage cells in the bone marrow. DYSERYTHROPOIESIS Qualitative dyserythropoiesis (Figs 1 and 2) may include ringed sideroblasts, multinuclear fragments, bizarre nuclear shapes, internuclear bridging, mitosis, abnormal dense chromatin or fine chromatin with asynchronous cytoplasm, and abnormal cytoplasmic features (intense basophilia, Howell-Jolly bodies, ghosted cyto- plasm). Anisocytosis, poikilocytosis, nucleated red blood cells, and acanthocytes may be seen on examination of the peripheral blood smear.'la It has been recognized for years that there are several types of iron granules in the cyto- plasm of erythroid These ferritin aggregates are seen in normal marrows in a variable percentage of normoblasts (usually less than 50%) and rarely exceed 4 gran~les/cell.'~ The occurrence of 5 or more granules is consid- ered pathologic (Fig 3) and when these granules comprise more than one third of the nuclear rim, the term "ringed" sideroblast has been sed.".^^ Ringed or abnormal sideroblasts can be found in a variety of hematologic conditions as well as in MDS. The disruption of mitochon- dria and observed changes in heme synthesis are the result of ineffective erythropoiesis, pre- 4 Seminars in Oncology, Vol 19, No 1 (February), 1992: pp 4-13 CLASSIFICATION OF MYELODYSPLASTIC SYNDROMES mature erythroid destruction, and refractory anemia. Quantitative changes may include the presence of an increased percentage of ringed sideroblasts (usually > 15% of all erythroid nucleated cells) and erythroid precursors comprising between 5% and 50% of bone marrow cells. If erythroid precursors account for greater than 50% of bone marrow cells and there are more than 30% blasts, then the diagnosis is erythroleukemia. In the FAB proposals,' refractory anemia (RA) was differentiated from refractory anemia with ringed sideroblasts (RARS) by the presence of more than "15% ringed sideroblasts of all nucleated cells in the marrow." Subsequent to this publication considerable confusion arose. GaltonI6 stated that the "main criterion was 15% of bone marrow erythroblasts." But as noted by Juneja et al," the majority of cases of RARS had greater than 20% ringed sideroblasts (median, 40%). In the Cazzola" series all patients had ring sideroblasts greater than 15% of untreated red cells. With appropriate nuclear counter stains for erythroid precursors, it seems reasonable that 15%ringed sideroblasts of erythroid cells might be the lower limit to include such patients as RARS. DYSGRANULOPOIESIS Abnormalities of granulocytes are common in MDS and are present in both the peripheral blood and bone marrow. The most common abnormalities are hypogranulation (Fig 4) that may be associated with a negative peroxidase reaction, and hyposegmentation of the polymorphonuclear leukocytes with chromatin condensation (Pelger-Huet like anomaly) (Fig 1). In some cases granules may be absent and the polys are referred to as agranular. A classification of this abnormality has been proposed by Hast et allyfor evaluation of dysgranulopoiesis in MDS. The defect in granulation may be seen only in myelocytes early in the course of disease. Occasionally, the chromatin appears clumped where blocks of chromatin are separated by a clear space, leading to an appearance of nuclear fragmentation associated with a loss of segmentation. Such clumped chromatin pattern has been associated with MDS and myeloproliferative disorders.'"-22 5 In 1984, Langenhuijsen' described the presence of granulocytes with a nuclear hole (ringshaped nuclei) in patients with myeloproliferative and myelodysplastic diseases. Van der Weide et alZ4observed ringed granulocytic nuclei in 32% of MDS cases. These cells probably represent a transitional stage to the band form (acquired Pelger-Huet formation) and are considered a sign of abnormal maturation. In addition, so-called nuclear "sticks" can be noted, particularly in cases of secondary MDS or therapy related MDS. In the bone marrow persistent cytoplasmic basophilia of the rim of the cell may be evident as well as abundant azurophil granules or larger granules than usual. Moreover, the function of neutrophils may be affected in MDS patients. Phagocytic adhesion, chemotaxis, and microbicidal capacities may be impaired, but no correlation has been found between the presence and degree of hypogranulation and neutrophil function.25v26 DYSMEGAKARYOCYTOPOIESIS Common abnormalities of megakaryocytes include micromegakaryocytes (Fig 5), multiple small nuclei separated by strands of nuclear material, and large mononuclear cells with dysmorphic nuclear features. To enhance the ability to recognize micromegakaryocytes the use of the CD41 monoclonal and antifactor VI11 antibody*' may be helpful. The 5q- syndrome is frequently associated with an abnormality of megakaryocytes, which are usually small, with a single eccentric round nucleus. Dysmorphic features have been reported and classified by Jinnai et a12'for the evaluation of dysmegakaryocytic features in MDS-associated AML. In addition, a recent study by Wong and Chan" recognized hypogranular megakaryocytes in 80% of MDS. DYSMONOCYTOPOIESIS Mature monocytes and their precursors can be identified in the bone marrow and peripheral blood film by use of esterase stains (usually the double esterase technique). This technique allows for an evaluation of the monocyte clonal proliferation and an estimate of the threshold of the monocyte population. It also permits one to recognize dysmorphic monocytic features (Fig 6) which may be observed in the more mature 6 \- GOASGUEN AND BENNETT 7 -`.. Fig 1. Anisocytosis and hypochromic red cells; agranular neutrophils with condensations of nuclear chromatin (pseudoPelger-Huet cells); giant platelets. Peripheral blood. MayGrunwald-Giemsa (MGG) stain. Fig 2. Dyserythropoiesiswith nuclear budding and internuclear bridging. Bone marrow, Wright-Giemsa stain. Fig 3. Many abnormal sideroblasts with multiple granules (ringed forms) in both immature and mature erythroblasts. Bone marrow, Prussian blue reaction. Fig 4. Hypo- and agranular myelocytes, metamyelocytes and neutrophils. FAB type: Refractory anemia (RA). Bone marrow, MGG stain. cells but are frequently overlooked in the immature precursors. The monocytic population can also be demonstrated by monoclonal antibodies CD13 and CD14. THE CYTO-IMMUNOLOGICAL DIAGNOSIS OF MDS The diagnosis of MDS may be enhanced by the application of certain cytochemical and immunocytochemical techniques. The peroxidase or Sudan Black B reaction may confirm the myeloid origin of blast cells; nonspecific esterase or a double esterase reaction can identify early monocytic precursors and differentiate these cells from poorly granulated myelocytes. Double esterase stains'" can also distinguish a population of early myeloidimonocytic cells (by the presence of both granulocytic and monocyte esterase) in marrows. Similar stained cells have been described in FAB M4 (acute myelomonocytic leukemia). Immune marker analysis for myeloid and lymphoid cells may provide insight into lineage association of acute leukemias and has been described in previous publications.31.'2 In megakaryocytic dysplasia the abnormally small megakaryoblasts ("dwarf cells") may resemble lymphoid precursors ("L," blasts). These cells can be recognized with immunocytochemistry on air dried smears with a CD41 antibody revealed by alkaline phosphatase anti alkaline phosphatase (APAAP) technique." Lymphoid blasts can be confirmed by a CD34 monoclona~l . antibody or by CDl9 and CDlO antibodies." Erythroid precursors may be diagnosed h!. ;i glycophorin A antibod), and immature m!cloid A CLASSIFICATION OF MYELODYSPLASTIC SYNDROMES 7 Fig 5. Mononuclear dysplastic megakaryocyte ("dwarf form"), hypogranular myelocytes, promyelocytes and basophilic erythroblast. Bone marrow, MGG stain. Fig6. Hypogranular neutrophils, several blasts, dyserythropoiesis and monocytes. Bone marrow, MGG stain. Fig 7. Type I, type I1 blasts (a few granules, less than 20) and blast with at least 20 granules ("type la").Note absence of golgi zone. Bone marrow, MGG stain. progenitors may be quantified by using a CD13, CD14, and CD33 monoclonal antibody Because expression of CD13 and CD33 antigens on immature myeloid cells may be variable, some a u t h o ~ s ~r'e.c~om~ mend using a mature/ immature myeloid ratio. Guyotat et alAbused a CD34 antibody that was only positive in refractory anemia with excess blasts cases and was significantly associated with progression to leukemia and short survival. Moreover, the significance of CD34 positive cells in AML has recently been reported in 96 adult patients, demonstrating a lower complete remission rate after intensive cytoreductive therapy (59% v 87%).j4The goal of such investigations has been to classify the lineage of blast cells, because the prognosis of such patients has been shown to correlate with the number of CD34 positive cells. Fig 8. Hypercellular bone marrow with numerous dysplastic mononuclear and hyperlobated megakaryocytes, containing pale cytoplasm. Note: so-called "mummified cell." Hematoxvlin and eosin stain. BLAST CELL CHARACTERISTICS IN MDS The FAB classification of MDS established criteria for the definition of blast cells.'-' Type I blasts are defined by the absence of azurophil granules; type I1 blasts have identical features but contain "a few primary (azurophil) granules" (Fig 7). The FAB group did not define the upper limit of how many granules could be present. Potentially, this could result in ambiguity in distinguishing myeloblasts from promyelocytes and might explain the variability in the MDS subclasses reported in the literature. The percentage of blasts in the bone marrow is the single most important prognostic factor in MDS, both in terms of overall survival as well as leukemic transformation. The FAB classification recognizes three groups of patients in terms a GOASGUEN AND BENNElT of percentage of blasts: cases with less than 5% blasts, cases with 5% to 20% blasts. and patients with 21% to 30% blasts. However, a study by Sanz et al'j demonstrated a survival difference between patients having 5 % to 10% blasts from those with 11% to 20% blasts. Moreover, it may be difficult differentiating promyelocytes and hypogranular myelocytes. In view of this, we recently introduced3' another blast cell termed "blast type 111," for myeloblasts with more than 20 azurophilic granules in the cytoplasm and not displaying a golgi zone (Fig 7). In a series of 18patients with MDS," we examined the prevalence of hypergranular myeloblasts (type 111) and detailed the concordance of observers as well as the impact of counting these cells among agranular blasts (type I) and granular blasts (type 11) on survival and leukemic progression. Our data suggest that these newly identified blast cells (type 111) may be helpful in identifying a subset of patients with a poor prognosis. BONE MARROW HISTOLOGY A bone marrow biopsy is strongly recommended in the evaluation of MDS and provides an excellent appreciation of the cellularity (Fig 8). For example, in cases of hypocellularity associated with pancytopenia, patients with MDS might be confused with aplastic anemia, even if features of mild dysmyelopoiesis are observed. The following criteria may be useful in diagnosing hypocellular MDS? abnormal localization of immature precursors (ALIP) located centrally in the medullary tissue instead of lining the endosteal surface; an increase of immature myeloid precursors; an island of erythroblastic precursors; and micromegakaryocytes and megakaryoblasts. which may be identified by the CD41 or factor VI11 monoclonal antibody. Myelofibrosis may be present in therapyrelated MDS but is not a common feature of primary MDS.4"4'Primary MDS may be associated with increased megakaryopoiesis, absence of organomegaly, and comparatively long patient survival. Such characteristics distinguish these cases from those previously described as acute myelodysplasia with myelofibrosis and malignant myelosclerosis." CLASSIFICATION OF THE MYELODYSPLASTIC SYNDROMES Refractor),Anemia Characteristically,patients with RA have anemia, which is the hallmark of disease. The anemia is refractory with an absolute low reticulocyte count. may vary from mild to severe, and is not related to age. Granulocytopenia and/or thrombocytopenia may be minimal or absent. The bone marrow usually shows erythroid hyperplasia and dysmegakaryocytopoiesis may be absent. Agranular or hypogranular neutrophils may or may not be observed in the peripheral blood. Blast cells are usually not present in the peripheral smear (or very rarely, less than 1%) and by definition, are less than 5% in the bone marrow. Ringed sideroblasts are infrequent and are always less than 15% of erythroid marrow cells. RA accounts for approximately 17% of cases of MDS. Refractory Anemia With Ringed Sideroblasts or Acquired Idiopathic Sideroblastic Anemia There are similar features to RA except that there are greater than 15% ringed sideroblasts in the bone marrow. The blood cell volume is frequently greater than 100 fL and the bone marrow may reveal punctuated erythrocytes and erythroid precursors with an empty and lamellar cytoplasm. The marrow blast cells are always less than 5%. When ringed sideroblasts greater than 15% are associated with an excess of blasts (more than 5%), the syndrome is classified as refractory anemia with excess of blasts (RAEB) according to the FAB definition. In RAS (without blasts) leukemic evolution is rare, because the sideroblastic cell clone is relatively stable. When the disease progresses, the pathological cell clone increases in number and proportion, and ringed sideroblasts may represent as many as 80% of erythroid cells. In a study of 94 patients with RARS, Gattermann et ai" described sideroblastic anemia with abnormalities confined to dyserythropoiesis. and RARS with additional dysplastic features of granulopoiesis andior megakaryopoiesis. This study showed a striking difference in the risk of leukemic transformation between the mu populations (5-year cumulative rate 1.9% I' 4 8 5 ) and overall survival (5-year survival 69% 1. 1 Y ' i J. i CLASSIFICATION OF MYELODYSPLASTIC SYNDROMES Thcse results emphasize the differences between pure sideroblastic anemia and sideroblastic anemia associated with other dysplastic lineage features. Lastly, one case of RARS evolving to chronic myelomonocytic leukemia (CMML) associated with inv(12) has recently been published" but the presence of dysgranulopoiesis was not noted. Refiactoiy Anemia WithExcess of Blasts RAEB is associated with conspicuous changes in granulocytes, which are hypo- or agranular, sometimeswith abnormal chromatin or segmentation. Thrombocytopenia is common, but is usually mild. Occasional blasts may be present in the peripheral blood but are always less than 5%. The bone marrow is usually hypercellular with 5% to 20% blasts (type I and type 11). In some cases type I11 blasts have been described3' and may portend a worse prognosis. If included with type I and type I1 blasts they permit a change in the diagnosis in some cases. RAEB progresses more frequently to AML than RA and RARS. Moreover, the presence of abnormally localized immature myeloid precursors in the trephine biopsy has been described by Tricot et a1444a5s an adverse prognostic factor. Refractory Anemia WithExcess of Blasts in Transformation RAEB in transformation (RAEB-t) includes cases with the same dysmorphic features as RAEB but the percentage of blast cells is greater than 5% in the peripheral blood and/or is 21% to 30% in the bone marrow. When the percent of marrow blasts approaches 30% it may be difficult to differentiate RAEB-t from AML. In such cases, type I11 blasts should be considered, because their identification may change the diagnosis to AML.'* Weisdorf and coworkersJhdescribed five patients with the features of RAEB but with occasional Auer rods. The median survival was 14 months (range. 2 to 27 months) which did not 9 differ significantly from RAEB as described by others. To recognize this entity the FAB group has included RAEB (5% to 20% of blasts) with Auer rods in the RAEB-t group. In younger patients ( <45 years) it is likely that this variant would rapidly evolve to overt AML. As depicted in Tables 1 and 2 the median survival and leukemic transformation rate of MDS subclasses may vary. Differences evident among these results may be secondary to the identification of types of blasts and the number of patients. However, three findings appear relevant: (1) survival is correlated with the presence of type I blasts in the marrow, as demonstrated by Sanz et al"; (2) the addition of type 111 blasts portends a worse prognosis3K;and (3) the overall leukemic transformation rate for MDS is approximately 20%.47In patients with RAEB-t, the percent of leukemic transformation may vary from approximately 50% to loo%, however. In the initial FAB proposals for MDS it was felt that the presence of 5% or more blasts in the peripheral blood film and a bone marrow that fulfilled criteria for MDS (less than 30% blasts) would warrant a diagnosis of RAEB-t. However. the observation that some patients presenting with greater than 30% of peripheral blood blasts and less than 30% marrow blasts evolved to AML within 2 months" suggests that an upper threshold of 20% to 30% marrow blasts would be reasonable to maintain for RAEB-t. Chronic Myelomonocytic Leukemia There continues to be controversy over the definition of CMML and the inclusion of this category among the MDS. As noted by Galton'h some patients with chronic myelogenous leukemia (CML) may have monocytosis greater than 1 x 10y/L. In contrast to classical CMML. however. such cases appear to have more immature granulocytes and less dysplasia. For the majority of cases of CMML the Author Varella et aim Goasguen et aid7 Third MIC'2 Table 1. Median Survival (months) of Patients with MDS Overall RARS RA RAEB RAEB-t CMML Median Survival 53 38 13 45 32 19 51 50 11 3 11 5 17 15 11 26 19 31 Number of Patients 56 503 1081 10 Author Varella et al" Goasguen et al" Third MICU Table 2. Percent LeukemicTransformation of MDS RARS 12 3 8 RA RAE6 15 41 8 20 12 44 RAEB-t 75 53 60 CMML 33 23 14 GOASGUEN AND BENNETT Overall Transformation Acute Leukemia 28 17 23 peripheral blood and bone marrow fulfill the criteria for MDS (variable degrees of trilineage dysplasia) and show the classical chromosomal abnormalities. Monocytes and precursors can be identified in the bone marrow by use of esterase stains (usually a double esterase technique). Although the minimal monocyte count for CMML was established at 1 x 109/Lsome authors have accepted a diagnosis at a lower threshold The continued inclusion of CMML in the subtypes of MDS should be based on a unique outcome (either responsiveness, survival, or leukemicprogression) similar to those of RAEB. However, a review of 175 patients with CMML showed a survival range of 11 to 60+ Stornolio et al" demonstrated a major role for blast percentage on survival but not for progression to AML. Fenaus et als2aconfirmed these observations, whereas Worsley et a15' emphasized the biologic significanceof elevated leukocytes and/or monocytes. In Storniolo's series'' patients with more than 0.6 x 109/Lmonocytes and less than 5% marrow blasts had a median survival of 52.5 months, whereas those with 5% to 20% blasts had a median survival of 15.5 months (similar to RAEB). In a series of 107CMML cases, Fenaw et a152also noted that patients with an excess of blasts had a short survival, similar to Storniolo's observations.Worsley et alS2observed that monocytosis greater than 2.6 X 109/Lcorrelated with a poor survival (11 months). The "modified Bournemouth" score was useds4 and patients with high monocyte and neutrophil counts and a high "modified" score had a clinical course resembling that of RAEB. The presence of unexplained monocytosis, the absence of the Philadelphia chromosome (Ph) or bcr-ab1fusion gene product in a patient with cytopenia(s) should alert one to consider a diagnosis of CMML." However, there will still be a minority of patients who do not have the Ph` chromosome but demonstrate an abnormal bcr-ab1gene. Laboratory and clinical features of these patients closely resemble Ph+ CML. Preliminary results from one stud$' suggest a similar response to interferon alfa. Galton" has classified these disorders on morphologic +grounds as Ph CGL, Ph-CGL, and CMML. Finally, there remains a minority of patients with elevated leukocyte counts but lacking the Ph` chromosome and bcr-ab1 fusion gene. Both Galton and Bennett (unpublished observations) propose that the term atypical CML be reserved for those cases that would have been classified as MDS (usually RAEB). The major distinction is a significant leukocytosis (above 15 X 109/L) with granulocytic dysplasia. AML WITH TRlLlNEAGE DYSPLASIA Because MDS may progress to overt AML in 15% to 20% of cases, it has been suggested that many so called "de novo" AML could represent progression from MDS not previously recognized. The adverse clinical significance of morphologically dysplastic leukemic cells as described in MDS occurring in primary AML has recently been reported by several investigat i o n ~ . ~In. ~o~ne series 15% of AML cases demonstrated trilineage myelodysplastic features (TMDS) and the remission rate was inferior to AML patients without TMDS.56 In another series2*that focused only on dysmegakaryocytopoiesis (DysM) 12% of 95 cases of AML had DysM, with 75% occurring in FAB type M4. Again the complete remission (CR) rate was lower in cases with DysM (14%) compared to those without (82%). In both series TMDS or DysM were not observed in FAELM3. This finding was confirmed by our experien~e.~H'owever, it appears that dysgranulopoiesis (DysG) is the most significant factor. In our series the CR rate of 336 AML cases was 57% when DysG was present, compared to 71.5% when absent ( P = 0.018). Chromosome data were not available in these retrospective studies.28.sN6 onetheless. we demonstrated that A. -- CLASSIFICATION OF MYELODYSPLASTIC SYNDROMES 11 dysplasia in FAB-M1 was associated with an abnormal karyotype and with a low CR rate.s7 MYELODYSPLASTIC SYNDROMES IN CHILDHOOD Although MDS have been described prima- rily in elderly patients and more recently in young similar biological and clinical features have been observed in ~hildren."~v'an Wering and colleague^^^ described three cases (2 RAEB-t and 1 CMML) with dysmegakary- opoiesis, hypogranular neutrophils, and a hyper- cellular marrow. Auer rods were present in one case. A study by Creutzig et ala of 21 cases (4 RAEB, 16 RAEB-t, and 1 CMML) revealed evidence of dyserythropoiesis and dysgranulo- cytic features in each case. Dysmegakaryopoie- sis was observed in the majority of patients, and Auer rods were present in 3 of the 16 RAEB-t. The median age was 11 years (range, 2 to 16 years), and the authors concluded that children with MDS might benefit from more aggressive treatment but in general, the survival rate was poor and similar to that observed in adults with MDS. Brandwein et a16' reported 14 cases of primary MDS (4 RA,2 RAEB, 1 W B - t , 7 CMML), 4 of whom were from two pairs of siblings. The median age was 7 years (range, 1to 17years); however, this group was more heterog- enous because 7 of the 14 children had CMML. These studies demonstrate that MDS can be diagnosed in children using the same criteria utilized in adults. The precise frequency is still unclear but MDS may account for approxi- mately 1% to 3% of childhood malignancies. The incidence appears to be increasing with the description of secondary or therapy related myelodysplastic syndromes in children6*and in MYELODYSPLASIA AND HUMAN IMMUNODEFICIENCY VIRUS-RELATED DISEASE Dysplastic maturation of hematopoiesis is a common finding in patients with human immu- nodeficiencyvirus (HIV) infection, and dysplastic features in the bone marrow have been described by several authors. Megaloblastic hematopoiesis with dyserythropoiesis, a left shift in granulocytic precursors and a marked increase in marrow megakaryocytes were reported by Spivak et aiM in 12 HIV-infected patients. In addition, dysplastic bone marrow features were described by Schneider et a165in 8 patients. The latter authors demonstrated that all three hematopoietic cell lines were involved in each of the HIV-infected individuals. Karcher et a1@reported on 216 bone marrows in 178 HIV-infected patients. The most common findings were hypercellularity (53% of specimens) and dysplasia involving at least one cell line (69%) with erythrocytic, megakaryocytic, and dysgranulocytic dysplasia in 56%, 31%, and 18% of specimens, respectively. Dyserythropoietic features included multinucleation, nuclear irregularity, and internuclear chromatin bridge formation. Megakaryocytic dysplasia, such as dwarf forms, nuclear hyposegmentation, and nuclear fragmentation was common. The granulocytic series showed asynchrony between nuclear and cytoplasmic maturation; occasional marrow aspirates exhibited multinucleation or hypogranular maturing cells. The mechanism(s) for HIV-related myelodysplasia is not clear. Drug toxicity, a secondary effect of opportunistic infections, or HIV infection itself have all been proposed as causative factors. Karcher et alMreported a significant correlation between myelodysplasia and Centers for Disease Control class IV disease and a history of opportunistic infection. These authors concluded that myelodysplasia in HIVinfected patients is probably directly related to HIV infection, which worsens with disease progression and is not a side effect of therapy.66It should be emphasized that dysplastic morphologic changes in HIV-infected patients do not necessarily have the same clinical implications as myelodysplasia in the non-HIV setting in regard to the evolution to acute leukemia.65 REFERENCES 1. Block M, Jacobson LO, Bethard WF: Preleukemic acute leukemia. JAMA 152:1018-1023,1953 2. Rheingold JJ, Kaufman R, Adelson E, et al: Smouldering acute leukemia. N Engl J Med 268:812-816, 1963 3. Bomford RR, Rhodes CP: Refractory anaemia. I. Clinical and pathological aspects. 11. Aetology and treatment. Q J Med 10:174-281,1941 4. Vilter RS, Will JJ, Jarrold T: Refractory anemia with hyperplastic bone marrow (a regenerative anemia). Semin Hematol4:175-193, 1967 12 5. 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