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Transient myeloproliferative disorder with erythroid differentiation in Down syndrome.

The transient myeloproliferative disorder (TMD) of Down syndrome, also known as transient abnormal myelopoiesis, characteristically manifests in the first few days of life, with numerous circulating blast cells exceeding the number of blast cells in the bone marrow and spontaneous resolution within a few weeks. (1) Because of close resemblance to hematologic malignancy, some authors choose to designate this self-limited entity as acute myeloid leukemia with spontaneous remission. (2) The blast phenotype in TMD is variable, but the immature cells have usually been positive for platelet-specific antigens CD41, CD42b, and CD61, for panmyeloid antigens in some cases, frequently for the stem cell marker CD34, and often coexpressed CD7. (2-4) Molecular studies have demonstrated an expression of erythroid-specific genes in blast cells of TMD. (5) Based on immunophenotypic analysis and recent molecular studies, the cell of origin is believed to be committed to the megakaryocytic lineage or is derived from a putative common precursor with a potential of differentiation along both megakaryocytic and erythroid pathways. (5)

Despite the accumulated evidence of dual megakaryocytic and erythroid differentiation, a TMD with an exclusive commitment to erythroid lineage has not been documented. The condition described herein was initially diagnosed as consistent with TMD, pending anticipated spontaneous resolution. Immunophenotypic analysis, however, showed a striking deviation from the hitherto described patterns with an almost exclusive bright expression of glycophorin A. The appearance of a large number of markedly dysplastic erythroid forms in the peripheral blood suggested the possibility of a rare form of TMD with erythroid differentiation.

REPORT OF A CASE

A male neonate with typical stigmata of Down syndrome was born full term after an uncomplicated pregnancy. The liver was slightly palpable at birth but the spleen and lymph nodes were not palpable. Karyotyping performed from a peripheral blood specimen revealed 47, XY, trisomy 21. On the first day postpartum, the patient's hemoglobin was 11.7 g/dL with a red blood cell count of 2.9 x [10.sup.6]/mL. His white blood cell count was 27 700/[micro]L with 61% blast cells, 10% myelocytes, 2% metamyelocytes, 5% band neutrophils, 9% segmented neutrophils, 10% lymphocytes, and 3% monocytes. The platelet count of 17 000/[micro]L triggered an order for platelet transfusion to prevent any hemorrhagic event in his condition. A tentative diagnosis of a TMD was rendered. To monitor the further development of the patient's disorder, a complete automated blood cell count and a differential cell count were performed almost every day until disappearance of blast cells and other atypical cells. On days 4 and 5 postpartum, hematopathologic evaluation of the circulating blast cells, consisting of cytochemical studies and flow cytometric analysis, respectively, was performed on a peripheral blood sample. Daily monitoring of the peripheral blood picture revealed 2 waves of abnormal cell production. Already during the first wave, markedly dysplastic erythroid precursors in different stages of maturation started to appear and their numbers gradually increased as the blast cells decreased in number. A similar dynamic was observed during the second wave that ended on postpartum day 35 by virtual disappearance of circulating abnormal cells. The results obtained by special studies led to the reevaluation of the original diagnosis as an erythroblastic disorder of undetermined prognostic significance. The patient received no antileukemic treatment, and bone marrow examination was not performed for lack of parental consent. He has received, however, a total of 8 platelet transfusions until the platelet counts stabilized above 30 000/[micro]L around the time of spontaneous resolution. Since the onset of remission in the neonatal period, the child has reportedly not experienced any major illness and is well 5 years after diagnosis.

PATHOLOGIC FINDINGS

Morphologic and Cytochemical Studies

Smears of peripheral blood were prepared by conventional manual slide technique and stained by Wright stain or various cytochemical staining methods. Examination of the patient's peripheral blood sample on the first day post partum revealed the presence of numerous blast cells with high nuclear-to-cytoplasmic ratio, irregular nuclei, finely reticular chromatin, and 1 to 4 nucleoli (Figure 1, A and B). The blast cells had a moderate amount of light azurophilic cytoplasm with small blue or purple granules and occasional tiny vacuoles (Figure 1, A and B). The blast morphologic analysis was otherwise not characteristic of any particular cell lineage. Cytochemical stains, including myeloperoxidase (Figure 1, B), Sudan Black B, and periodic acid--Schiff, were negative. Many of the blast cells were faintly positive for [alpha]-naphtyl butyrate esterase (Figure 1, C). The staining for this nonspecific esterase was more intense near a nuclear notch in the Golgi region.

[FIGURE 1 OMITTED]

During the first wave of this disorder, numerous markedly abnormal erythroid cells appeared in the peripheral blood as the circulating early blast cells decreased in number (Figure 1, D). These erythroid forms had polychromatophilic to ortochromic cytoplasm displaying occasional vacuoles. The dysplastic features included nuclear budding, bilobed or multilobulated nuclei, and occasional binucleation. Despite the more mature cytoplasmic features, the nuclear-to-cytoplasmic ratio was disproportionately high and many of the dysplastic nuclei still exhibited 1 or 2 indistinct nucleoli. Especially during the second wave, more numerous nucleated red blood cells with decreased nuclear-to-cytoplasmic ratio were noted in the peripheral blood smears.

Monitoring of the patient's condition with regular differential counts on peripheral blood smears allowed assessment of the dynamics of abnormal cell generation (Figure 2). The absolute number of immature cells that included both blast cells and abnormal blastlike erythroid precursors reached a peak between days 5 and 7 postpartum with a maximum of 36 500/[micro]L on day 7. On day 8, the numbers of atypical cells decreased considerably and continued to fall until day 11 when the differential count registered 2926/[micro]L atypical cells. The counts then were continuously below 5000/[micro]L for 4 consecutive days. The second wave showed similar characteristics to the first one, with blast cells predominating in the waxing phase. The absolute count of early blast cells and dysplastic erythroid precursors during this second episode reached 25 800/[micro]L on day 22. After that, the abnormal circulating cells gradually decreased in number with only few circulating dysplastic cells present on days 35 to 38 postpartum.

[FIGURE 2 OMITTED]

Immunophenotypic Analysis by Flow Cytometry

A peripheral blood sample on postpartum day 5 was prepared by standard methods for immunophenotypic study by flow cytometry using Coulter EPICS XL-MCL apparatus. A stained cytospin made from the final cell suspension showed predominantly blast cells with multiple nucleoli and a moderate amount of blue cytoplasm as well as dysplastic erythroid cells with markedly irregular nuclei containing 1 to 3 nucleoli. Because of the high nuclear-to-cytoplasmic ratio and the presence of nucleoli, many of these dysplastic erythroid forms still retained blastlike appearance. A single region containing approximately 66% of all events collected was analyzed (Figure 3). The cells in this region had medium forward scatter and low-to-medium side scatter characteristics. Most cells (96%) in this gate were brightly positive for glycophorin A, and a distinct subpopulation (34%) dimly coexpressed CD45. The cells in the gated region were negative for all other antigens tested, including HLA-DR (0%), CD34 (3%), CD13 (3%), CD33 (3%), CD14 (0%), CD2 (3%), CD3 (2%), CD4 (3%), CD5 (1%), CD7 (4%), CD8 (0%), CD10 (0%), CD19 (0%), CD20 (0%), CD22 (0%), CD41 (3%), CD61 (1%), and CD71 (9%). (All antibodies were obtained from Coulter Corp, Miami, Fla.) This phenotype was consistent with abnormal erythroid cells and was compatible with the morphologic findings and weak positivity with nonspecific esterase.

[FIGURE 3 OMITTED]

COMMENT

One of the unique hematologic abnormalities seen in neonates with Down syndrome is TMD. This faithful mimicker of congenital acute leukemia occurs almost exclusively in the first few days of life (4,5) and spontaneously remits after a few weeks. (5) Occasionally, however, TMD has preceded acute megakaryoblastic leukemia (AML-M7) after a period of remission lasting several months to years. (6,7) Based on the analysis of methylation patterns of chromosome X, it has been proposed that TMD represents a clonal proliferation of immature hematopoietic precursor cells. (8,9) Besides the clinical and morphologic resemblance to acute leukemia, the apparent monoclonality of the disorder contributes to the mystery of spontaneous resolution. The blast cells of TMD have a varied phenotype, but expression of platelet-associated antigens is one of the more consistent features. (3,4) Erythroid-specific genes have also been demonstrated in blast cells of some TMD cases, (5) and dyserythropoiesis has been identified in the bone marrow in a few cases assigned to the category of acute myeloid leukemias with megakaryocytic or erythroid differentiation, some of which may have been self-limited. (2) In addition, TMD is usually associated with either normal or increased platelet count, (1,3) although rare cases with marked thrombocytopenia have also been reported. (2)

The case described herein differed from other cases of TMD in several aspects. First, the blast cells did not have the usual phenotype because they lacked expression of megakaryocyte-specific antigens, myeloid markers, T-cell associated antigen CD7, or stem cell marker CD34. Second, the blast cells were strongly positive for glycophorin A. Third, the patient presented with marked thrombocytopenia that required multiple platelet transfusions, whereas decreased platelet count is not a common feature of TMD. The most interesting finding, however, was the morphologic evidence of exclusive erythroid differentiation with circulating dysplastic erythroid precursors that at certain time intervals during this disorder represented most atypical cells in the peripheral blood.

The lack of CD34 expression was somewhat unexpected because this stem cell antigen is expressed on early normal erythroid progenitors (10) and erythroblasts in most erythroleukemia (AML-M6) cases. (11) The flow cytometric analysis, however, was performed on day 5 postpartum at a time when dysplastic erythroid cells with more mature cytoplasmic features were already present in the peripheral blood. It is conceivable that CD34 might have been expressed on blast cells early in the disorder but was lost after the onset of maturation. The transferrin receptor (CD71) is normally expressed on erythroid progenitors through the reticulocyte stage. (10) Because the presence of dysplastic erythroid precursors provided clear evidence of erythroid differentiation, the essential negativity for CD71 (9%) is an aberrant finding consistent with an abnormal phenotype. The dim coexpression of CD45 on a subpopulation of glycophorin A-positive cells is suggestive of a subset of early blast cells with erythroid commitment sharing this common leukocyte antigen.

Similar dysplastic changes in the erythroid series can be seen in the bone marrow of individuals with congenital dyserythropoietic anemia. (12) The dysplastic nucleated erythroid cells in congenital dyserythropoietic anemia, however, do not circulate in the peripheral blood, where dyserythropoiesis manifests as anisopoikilocytosis and macrocytosis of mature red blood cells.

It is not known whether the neonatal episode of "dyserythroblastemia" was a transient peripheral manifestation of persistent dysplasia in the bone marrow or whether it was a harbinger of future dysplasia or leukemia in this patient. However, regular examinations of peripheral blood have recently shown normal values with normal red blood cell morphologic features and no anisocytosis. As stated earlier, a bone marrow examination was not performed during the disorder, and there is no current clinical indication for this procedure because the patient is asymptomatic. Myelodysplastic syndrome in Down syndrome, however, is often asymptomatic and is believed to be the precursor of acute myeloid leukemia. (13) Therefore, long-term follow-up of this patient had been instituted and remains in effect.

Accepted for publication August 22, 2001.

References

(1.) Nagao T, Lampkin, BC, Hug G. A neonate with Down's syndrome and transient abnormal myelopoiesis: serial blood and bone marrow studies. Blood. 1970;36:443-447.

(2.) Litz CE, Davies S, Brunning RD, et al. Acute leukemia and the transient myeloproliferative disorder associated with Down syndrome: morphologic, immunophenotypic and cytogenetic manifestations. Leukemia. 1995;9:1432-1439.

(3.) Hayashi Y, Eguchi M, Sugita K, et al. Cytogenetic findings and clinical features in acute leukemia and transient myeloproliferative disorder in Down's syndrome. Blood 1988;72:15-23.

(4.) Yumura-Yagi K, Hara J, Kurahashi H, et al. Mixed phenotype of blasts in acute megakaryocytic leukaemia and transient abnormal myelopoiesis in Down's syndrome. Br J Hematol. 1992;81:520-525.

(5.) Ito E, Kasai M, Hayashi Y, et al. Expression of erythroid specific genes in acute megakaryoblastic leukemia and transient myeloproliferative disorder in Down's syndrome. Br J Hematol. 1995;90:607-614.

(6.) Lin H-P, Menaka H, Lim K-H, Yong H-S. Congenital leukemoid reaction followed by fatal leukemia. Am J Dis Child. 1980;134:939-941.

(7.) Wong KY, Jones MM, Srivastava AK, Gruppo RA. Transient myeloproliferative disorder and acute nonlymphoblastic leukemia in Down syndrome. J Pediatr. 1988;112:18-22.

(8.) Kurahashi H, Hara J, Yumura-Yagi K, et al. Monoclonal nature of transient abnormal myelopoiesis in Down's syndrome. Blood 1991;77:1161-1163.

(9.) Miyashita Y, Asada M, Fujimoto J-i, et al. Clonal analysis of transient myeloproliferative disorder in Down's syndrome. Leukemia. 1991;5:56-59.

(10.) Moore MAS. The hematopoietic system and hematopoiesis. In: Knowles DM, ed. Neoplastic Hematopathology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:1-42.

(11.) Cuneo A, Van Orshoven A, Michaux JL, et al. Morphologic, immunologic and cytogenetic studies in erythroleukemia: evidence for multilineage involvement and identification of two distinct cytogenetic-clinicopathologic types. Br J Hematol. 1990;75:346-354.

(12.) Naeim F. Disorders of red blood cells. In: Naeim F, ed. Pathology of the Bone Marrow. 2nd ed. Baltimore, Md: Williams & Wilkins; 1998:396-433.

(13.) Creutzig U, Ritter J, Vormoor J, et al. Myelodysplasia and acute myelogenous leukemia in Down's syndrome: a report of 40 children of the AML-BFM study group. Leukemia. 1996;10:1677-1686.

From the Department of Pathology, University of South Alabama, Mobile, Ala.

Reprints: Peter Bozner, MD, PhD, Burch, McQuitty & West, Ltd, Professional Medical Corporation, PO Box 52009, Lafayette, LA 70705 (e-mail: docpeterboz@msn.com).
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Author:Bozner, Peter
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Apr 1, 2002
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