The patient was a 62-year-old woman with an approximately 50-year history of Gaucher disease who presented with progressive splenic enlargement and underwent evaluation for lymphoma. Complete blood count showed a white blood cell count of 3.8 × 103/μL; red blood cell count, 4.33 × 106/μL; hemoglobin, 9.8 g/dL; mean corpuscular volume, 71 fL; and platelets, 133 × 103/ μL. She had received no therapy for Gaucher disease since diagnosis.
A Wright-Giemsa–stained bone marrow aspirate smear revealed a marked increase in histiocytic cells characterized as Gaucher cells, which accounted for approximately 50% of marrow nucleated cells. These Gaucher cells had voluminous pale basophilic cytoplasm with a crinkled, striated appearance (Figure 1). Some Gaucher cells displayed erythrophagocytic activity with ingestion of mainly mature erythrocytes (Figure 1; inset shows a multinucleated Gaucher cell engulfing erythrocytes). Many Gaucher cells were overloaded with iron particles, as shown by Prussian blue stain on an aspirate smear (Figure 2; a Gaucher cell filled with erythrocytes as well as positive iron particles is shown in inset). A hematoxylin-eosin– stained section of the bone marrow biopsy demonstrated partial replacement with Gaucher cells (Figure 3). As on the aspirate smear, erythrophagocytosis was observed in Gaucher cells on the biopsy section (Figure 3, inset).
Gaucher disease is a rare autosomal recessive disorder characterized by hepatosplenomegaly, bone lesions, skin pigmentation, scleral pingueculae, and in later stages, anemia, leukopenia, and thrombocytopenia. Gaucher disease is a typical lysosomal storage disease resulting from an inborn deficiency of β-glucocerebrosidase, which leads to the accumulation of glycolipids in macrophages. On histologic review, large cerebroside-containing cells are found mainly in the spleen, liver, bone marrow, and lung. Central nervous system disease may also arise as a result of the accumulation of endogenous glycosphingolipid metabolites in brain tissue. At least 150 mutations of the β-glucocerebrosidase gene have been identified in patients with Gaucher disease, and there is a spectrum of disease expression and severity. Three clinical phenotypes are generally recognized: (1) type 1, the most common form, usually presents in adults, has an increased incidence in Ashkenazi Jews, and is not associated with neurological manifestations; (2) type 2, an acute infantile form, shows neurological manifestations, and patients with this type die in early childhood; and (3) type 3, a subacute juvenile variant, is also associated with neurological manifestations and may have a relatively rapid or prolonged clinical course. Based on the relatively indolent clinical course and nonneurological involvement, the current case represents type 1 Gaucher disease.
Lee and coworkers1 in 1967 described erythrophagocytosis seen in Gaucher cells. Their electron microscopic image showed portions of 3 erythrocytes surrounded by the wrinkled cytoplasmic features of a characteristic Gaucher cell. In their study, total body iron stores were increased, and Gaucher cells often contained increased iron. Iron metabolic studies were consistent with mild ineffective erythropoiesis. They thus suggested that the iron in Gaucher cells arose from erythrophagocytosis and that the erythrocyte was the source of cerebroside in the Gaucher cells. In another electron microscopy study published in 1970, Hibbs et al2 also reported frequently finding erythrocytes within the cytoplasm of large Gaucher cells. Dense vesicles of variable size that appeared to be derived from erythrocyte particles also appeared inside Gaucher cells.
Biochemical and imaging work has established that the storage inclusions of Gaucher cells are composed of flat layers of crystallized glucocerebroside, as well as tubular structures consisting of twisted multilayers and flat layers. Naito et al3 reported that with electron microscopy the tubular structures were observed to be formed during the digestive process of erythrocytes. In one experiment, unaltered monocytes from patients with Gaucher disease developed tubular structures in their phagolysosomes after ingesting erythrocytes in vitro, thus becoming Gaucher cells. The mechanisms by which Gaucher cells are stimulated to become erythrophagocytotic are unclear, but may be due to altered cytokine activation.
The authors have no relevant financial interest in the products or companies described in this article.
Corresponding author: Endi Wang, MD, PhD, Hematology Laboratory, Department of Laboratory Medicine, University of California, San Francisco, 505 Parnassus Ave, Room M5224, San Francisco, CA 94143-0100 (email@example.com)