The patient was a male newborn, delivered by cesarean section at 32 weeks to a 25-year-old Hispanic woman. The mother, gravida 3, para 2, had received routine prenatal care prior to delivery. An ultrasound of the fetus at 31 weeks showed bilateral pleural effusions and ascites with polyhydramnios. Delivery was via cesarean section secondary to decreased/absent diastolic flow from placenta to umbilical cord. The fetus was born in respiratory distress. Apgar scores were 4 at 1 minute, 6 at 5 minutes, and 6 at 10 minutes. The patient had features that included low-set ears, bilateral transverse palmar creases, and a wide space between the first and second toes. Anasarca was present, most prominently on the chest, abdomen, and in the genitourinary tract. The skin over the face, chest, and back had petechial hemorrhages. A complete blood count disclosed the following values: white blood cell count, 29.3 x 10^sup 9^; red blood cell count, 3.67 M/(mu)L; hemoglobin, 131 g/L; hematocrit, 0.42; mean corpuscular volume, 113 fL; and platelets, 36 x 10^sup 9^/L. Peripheral blood examination showed the presence of a monotonous population of blasts with multiple prominent nucleoli, finely dispersed chromatin, and a high nuclear-cytoplasmic ratio. Blasts represented 50% of peripheral blood white blood cells. Nucleated red blood cells were present at a rate of 32 per 100 white blood cells and revealed irregular nuclear contour and double nuclei (Figure 1). Periodic acid-- Schiff stain demonstrated the presence of positive granules in the cytoplasm of nucleated red blood cells and some blasts (Figure 2). Cytogenetic evaluation of fetal blood revealed a 47,XY,+21 karyotype with no additional chromosomal abnormalities. Laboratory data confirmed that no immune-related hemolytic process was present. The neonate showed a progressively worsening clinical course and died approximately 52 hours after birth.
An autopsy was performed, revealing no internal organ anomalies. Examination of bone marrow obtained at autopsy showed more than 50% of erythroid precursors with changes similar to those seen in the peripheral blood smear, and more than 30% blasts as calculated from nonerythroid nucleated blood cells (Figure 3). The bone marrow blasts were similar to those seen in the peripheral blood smear.
What is your diagnosis?
Pathologic Diagnosis: Down Syndrome With Acute (Transient) Leukemia
In the current case, we describe a neonate with hydrops fetalis and acute (transient) leukemia diagnosed on the basis of peripheral blood, bone marrow, and cytogenetic studies. The findings showed features of erythroleukemia (FAB-M6), trisomy 21 with Down syndrome (DS) phenotype, no additional chromosomal abnormalities, and a clinically aggressive disease course.
Down syndrome is the most common autosomal chromosomal abnormality in newborn infants, with an incidence of 1 in every 700 live births. Most persons with DS have trisomy 21 present in all cells. However, 1% to 2% of newborns with DS exhibit a mosaicism, in which chromosomal constitutions other than trisomy 21, usually normal diploid cells, are present. The clinical manifestations depend on the tissues involved and the proportion of trisomic cells present.1
The incidence of leukemia is approximately 20 times greater in children with DS than in those without DS.1,2 A rare form of childhood leukemia, acute megakaryoblastic leukemia, is approximately 500 times more common in children with DS than in healthy children.3,4 It has also been reported that DS children have an abnormally high incidence of erythroleukemia.5 Bone marrow studies of children with DS and transient leukemia show thrombocytopenia and frequent involvement of the red cell lineage, as demonstrated by dyserythropoiesis and megaloblastic changes.4,5 There is an absence of other chromosomal abnormalities, including translocation t(1;22), an aberration usually found in acute myeloblastic leukemia patients without DS.4
In the past, the leukemia-like picture in neonates with DS or mosaicism for DS was not considered to be leukemia, because it was found almost exclusively during the first 4 years of life and the disease usually disappeared without therapy within 1 to 3 months.6 Instead, the condition was referred to as transient myeloproliferative disorder or transient abnormal myelopoiesis.2,6 Although still controversial, the term transient leukemia is currently more accepted.2,5,6 In the case described here, the peripheral blood smear and bone marrow features are consistent with erythroleukemia; however, the presence of DS without additional chromosomal abnormalities makes the diagnosis of transient leukemia more appropriate.
Recent evidence has indicated that transient leukemia in the newborn is a clonal disease.5,6 Evidence of the clonal nature of the disease favors the hypothesis that transient myeloproliferative disorder or transient leukemia represents a specific form of leukemia. Even though most cases show complete resolution, about 25% of DS infants who recover develop acute megakaryoblastic leukemia within 3 years. These acute megakaryoblastic leukemia blasts frequently have chromosomal abnormalities in addition to trisomy 21, suggesting that an additional mutational event may be necessary for the transformation.1,5
Leukemic cells in transient leukemia typically have fealures of megakaryoblasts. Cell size varies from 15 to 20 (mu)m. There is a small amount of basophilic cytoplasm and usually significant cytoplasmic budding. The cytoplasm may be agranular or it may contain a few fine, dark, red granules. One to 2 distinct nucleoli are typically seen.2 Interestingly, these megakaryoblasts also have features of early erythroid precursors, appearing to be a precursor cell with biphenotypic properties.5 Due to the clonal nature of transient leukemia, the morphologic features of the neonate's blasts are the same if there is a recurrence later in life. Some neonates have died with infiltration of blasts in various organs or were born with hydrops fetalis.2,6
When evidence of clonal proliferation is present, a fatal disease course may be seen. There have been several reports of hydrops fetalis in patients with transient leukemia, which may cause death in utero or severe disease at birth.3,5,7 The pathophysiology of hydrops fetalis is still unclear. Mechanisms associated with imbalance between intravascular or capillary hydrostatic pressure and transcapillary filtration may be responsible for these symptoms. De Groot et als hypothesized that "immune" hydrops fetalis manifests as a systemic fetal syndrome caused by hypoxia, resulting in liberation of cytotoxic factors leading to a generalized effect on fetal vascular endothelial cells. A similar mechanism may be responsible for hydrops fetalis in transient leukemia, in which hypoxia is produced by anemia resulting from the proliferation of leukemic cells.
A fetus with signs of hydrops must be considered critically ill and at high risk of intrauterine death. Chromosomal analysis is important in the evaluation of nonimmune hydrops, especially in the absence of anatomical abnormalities. Chromosomal aberrations will be found in 7% to 15% of cases of hydrops fetalis. Percutaneous umbilical blood sampling with rapid karyotyping and hematologic evaluation should be considered the standard of care in all cases.7
We are especially grateful to Connye Kuratko, PhD, for critically reviewing this manuscript and to Vijaj Tonk, PhD, for providing cytogenetic evaluation of this patient.
1. Bhatt S, Schreck R, Graham JM, et al. Transient leukemia with trisomy 21: description of a case and review of the literature. Am J Med Genet. 1995;58: 310-304.
2. Zipursky A, Brown EJ, Christensen H, et al. Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome. Clin Lab Med. 1999;19:157-167.
3. Zipursky A. Susceptibility to leukemia and resistance to solid tumor in Down syndrome. Pediatr Res. 2000;47:704.
4. 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.
5. Zipursky A, Poon A, Doyle J. Leukemia in Down syndrome: a review. Pediatr Hematol Oncol. 1992;9:139-149.
6. Lampkin BC. The newborn infant with leukemia. J Pediatr. 1997;131:176-- 177.
7. Hendricks S, Sorensen T, Baker ER. Trisomy 21, fetal hydrops, and anemia: perinatal diagnosis of transient myeloproliferative disorder? Obstet Gynecol. 1993;82 (pt 4, suppl 2):703-705.
8. De Groot C, Oepkes D, Egberts J, Kanhai HH. Evidence of endothelium involvement in the pathophysiology of hydrops fetalis? Early Hum Dev. 2000;57: 205-209.
Accepted for publication March 22, 2001.
From the Department of Pathology, Texas Tech University Medical Center, Lubbock, Tex.
Reprints not available from the authors.
Copyright College of American Pathologists Dec 2001
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