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Gaucher's Cells in Thalassemia


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  • 1. 1971 38: 457-462 EDWARD C. ZAINO, MARIO B. ROSSI, TUAN DUC PHAM and HENRY A. AZAR Gaucher’s Cells in Thalassemia Information about reproducing this article in parts or in its entirety may be found online at: Information about ordering reprints may be found online at: Information about subscriptions and ASH membership may be found online at: .Hematology; all rights reservedCopyright 2007 by The American Society of DC 20036. by the American Society of Hematology, 1900 M St, NW, Suite 200, Washington Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published semimonthly For personal use on November 19, 2010.www.bloodjournal.orgFrom
  • 2. From Mercy Hospital, Rockeille Centre, N.Y., and Francis Delafleld Hospital, New York, Gaucher’s Cells in Thalassemia BLoOD, OL. 38, No. 4 (OcTolsEn), 1971 457 By EDWARD C. ZAINO, MARIO B. Rossl, TUAN DUC PITAM, AND HENRY A. AZAR Gaucher or Gaucher-like cellsare de- scribed in the spleen and bone marrow of patient with thalassemia major, by light and electron microscopy. Theultra- structure shows intracytoplasmic tubules and phagocytosis of mature and imma- ture erythrocytes. The spleen has an increase in monohexosyl ceramide. These findings support the concept thatthe intracytoplasmic tubular material of the Gaucher’s cells is of extracellular origin. Erythrophagocytosis common in Gau- cher’s disease, chronic myelogenous leukemia, and thalassemia suggest that impaired catabolism of erythrocytes may give rise to the increased glucocerebro- side. T HE INTRACYTOPLASMIC GLUCOCEREBROSIDE ACCUMULA- TION’ gives the Gaucher’s cell its characteristic microscopic appearance. In Gaudier’s disease, it is as a result of a glucocerebrosidase deficiency2 and in chronic myelogenous leukemia itis presumed to be due to excessive granulo- cytic turnover.3#{176} Fig. 1.-Aspirated bone marrow. Gaucher cell is shown adjacent to a mega- karyocyte. x 1000. NY. Submitted February 24, 1971; recised May 12, 1971; accepted May 29, 1971. EDWARD C. Ziixo, M.D.: Director of Laboratories, Mercy Hospital, Rockville Centre, NY. MAsiso B. Rossi, M.D.: Pathologist, Department of Pathology, Mercy Hospital, Rockvilie Centre, NY. TUAN Duc PHAM, M.Sc.: Research Associate, Francis Dclii field Hospital, Columbia Unieersitij School of Medicine, Netv York, N.Y.HENRY A. AZAR, M.D.: Professor of Pathology, Kansas iIedical Center, Kansas City, Kan.s.; formerly Associate Professor of Pathology, Francis Delafield Hospital, Columbia University School of Medicine, New York, NY. For personal use on November 19, 2010.www.bloodjournal.orgFrom
  • 3. 458 ZAINO ET AL. Fig. 2.-Aspirated bone marrow, showing faint out- lines of the phagocytized ervthrocyte. x 1200. Ve are reporting the presence of Gaucher or Gaucher-likecells in thalas- semia, as demonstrated by light and electron microscopy. Evidence is pre- sented supporting a relationship between Gaucher’s cells and the phagocytosis and breakdown of ervthrocytes. CASE REPORT A 15-yr-old, white female was admitted to Mercy Hospital for splenectomy and anemia. A diagnosis of Cooley’s anemia was made atthe age of 43 years; at that time she had moderate hepatosplenomegaly. The patient had never had a blood transfusion prior to the hospital admission. Shecomplained of frontal headaches, palpitations, tiredness, and short- ness of breath. On physical examination she was small in size. Therewas pallor, scleral icterus, bossing of the parietal l)ones and prominence of the zygoma. The liver and spleen were enlarged; the liverwas 4 cm and the spleen 8cm below the costal margin. There was cardiac enlargement with agrade 4/6 systolic murmur, and a hepatojugular reflux. Fig. 3.-PAS-positive cells in tile spleen. X 320. For personal use on November 19, 2010.www.bloodjournal.orgFrom
  • 4. c.- . CAUCIIER’S CELLS IN TITALASSEMIA 459 Fig. 4.-Gaucher cell, showing eccentric nucleus, intracytoplasmic tubules, and a phagocytized erythrocyte. X 13,500. The lungs were clear to percussion and auscultation; there was no ankle edema present. Both parents are of Italian extraction and show evidence of thalassemia minor, with target cells, basophilic stippling, and no anemia. Her hemoglobin on admission was 6.5 g/100 ml. The peripheral blood smear showed hypochromia, target cells, anisocytosis, poikolocytosis, basophilic stippling, and nOrfllOblasts. She had a fetal hemoglobin of75%, increased A2 hemoglobin (8%), decreased fragilityto saline, a bilirubin of 4.0 mg, mainly indirect, and normal BUN, calcium, total protein, alkaline phosphatase, and SCOT. Xrays of the skull showed osteoporosis and characteristic “hair on end” appearance. The aspirated bone marrow, smears and sections, were very cellular, with many red cell precursors, hemosiderosis, and PAS-positive foam cells (Figs. 1 and 2). She was given two units of packed red cells and the spleen was removed. Sections of the spleen showed hemosiderosis and PAS-positive foam cells (Fig. 3). These cells were also present in the accessory spleen and a lymph node. The liver biopsy showed hemosiderosis and no foam cells. Electron microscopy showed the characteristic structure of Caucher’s cells, with many For personal use on November 19, 2010.www.bloodjournal.orgFrom
  • 5. Fig. 5.-(A) Tubular structures thatvary in density as vell asconfiguration. X 13,500. (B) Higher magnification of tile membrane-bound tubular structures and mitochondria. X 51,000. 460 ZAINO ET AL. moderate-sized tubules inthe cytoplasm (Fig. 5). The smooth endoplasmic reticulum was dilated and the mitochondria were at times swollen with fading cristae(Figs. 4 and 5). Some of these cells also showed phagocytosis of normoblasts and mature erythrocytes (Fig. 4). The spleen had a slight increase in giucocerebroside, 0.08 jimole monohexosyl cera- mide per gram of wet tissue. A control, surgically removed spleen, of an anemic hyper- bilirubinemic similar-aged female with hereditary spherocytosis and no Caucher cells in the spleen or bone marrow, had 0.06 mole monohexosyl ceramide per gram of wet tissue. The patient made an uneventful recovery; she was discharged and returned to school. Her hemoglobin gradually dropped, and she required blood transfusions13 mo after the splenectomy. MATEmALS AND METHODS Part of the bone marrow and tissue samples from the spleen werefixed in 6.25 phosphate- buffered glutaraldehyde (p1’ 7.6), postfixed in osmium tetraoxide (pH 7.4) washed with phosphate buffer dehydrated in acetone and embedded in epoxy resin (Durcupan, Fluka AG). The sections were cut with a Porter Blum microtone and transferred on formvar (polyvinyl formal plastic) coated copper grids, stained with uranyl acetate and lead citrate, and examined with a hitachi electron microscope. The bone marrow and tissue were also fixedin formalin and stained with hematoxylin and eosin and PAS. The bone marrow smears were stained with Ciemsa, tetrachrome,and PAS. The fresh-frozen spleen samples were sent to Dr. D. S. Fredrickson and Dr. H. R. Sloan at the National 1-leart and Lung Institute for lipid analysis. They were extracted with chloroform methanol and a silicic acid column. Cholesterol and esters were eluted with chloroform, and thenwith ethyl acetate. Acetone then completely removed all the mono-, di-, and trihexosvl ceramides from the column. Following alkaline methanolysis,the For personal use on November 19, 2010.www.bloodjournal.orgFrom
  • 6. GAUCHER’S CELLS IN THALASSEML 461 glycolipids were separated by Silica gel C thin-layer chromatography and quantitated by gas chromatography.7 DIscussIoN Foam cells have been described by light microscopy but not by electron microscopy in the spleen and bone marrow in Cooley’s anemia.8 PAS-positive material is present in the red cell9 of thalassemia as early as the erythroblast’#{176} and is regarded by Astaldi9 as a mucopolysaccharide resulting from an inherent red cell defect in carbohydrate metabolism. It was further postulated that the histiocytes had a similar defect.1’ The patient inthis report has classical beta thalassemia major. The foam cells in the bone marrow prior to blood transfusion indicates that they were not of donor-cell origin. There was phagocytosis of erythrocytes, reticulocytes, normoblasts, and characteristic tubular ultrastructure of Gaucher’s cells. The increase in glucocerebroside is significant in that there were only small scattered collections of these cells. The glucocerebroside increase in Gaucher’s disease is dependent on the degree of infiltration with Gaucher’s cells. These findings support the concept that the “Gaucher” cells that weare describing in thalassemia are identical to the previously described foam cells, and that they result from the breakdown of erythrocytes. The intracytoplasmic tubular material may represent incomplete catabolism of red cells, possibly their glycolipid-rich membranes.12 Engulfed erythrocytes are present in the Gaucher cells of Gaucher’s dis- ease13-16 chronic myelogenous leukemia,14 and, in this report, thalassemia. The intracytoplasmic red cell fragments, ferritin-like particles,14 and the iron in Gaucher’s disease’5 support the concept that the source of the cerebroside may be the phagocytized erythrocyte. ACKNOWLEDGMENT Lipid analyses of the spleens through the courtesy of Dr. D.S. Fredrickson and Dr. H. R. Sloan of the National Heart and LungInstitute, National Institutes of Health, Bethesda, Md. REFERENCES 1. Fisher, E. R., and Reidbord, H.: Caucher’s disease: Pathogenetic considera- tions based on electron microscopic and histochemical observations. Amer. J. Path. 41:679, 1962. 2. Brady, R. 0., Kanfer, J. N., Bradley, R. M., and Shapiro, D.: Demonstration of a defictncy of glucocerebroside-cleaving enzyme in Caucher’s disease. J. Clin. Invest. 45:1112, 1966. 3. Smith, W. C., Kaneshiro, M. M., Goldstein, B. D., Parker, J. W., andLukes, R. J.: Gaucher cells in chronic granulocytic leukemia. Lancet 2:780, 1968. 4. Kattlove, H. E., Williams, J. C., Cay- nor, E., Spivack, M., Bradley, R. M., and Brady, R. 0.: Caucher cells in chronic myelocytic leukemia: an acquired abnormal- ity. Blood 33:379, 1969. 5. Rosner, R., Dosik, H., Kaiser, S. S., Lee, S. S., and Morrison, A. N.:Gaucher cells in leukemia. JAMA 209:935, 1969. 6. Gerdes, J., Marathe, R. L., Bloodworth, M. B., and MacKinney, A. A.: Caucher cells in chronic granulocytic leukemia. Arch. Path. (Chicago) 88:194, 1969. 7. Kwiterovich, P. 0., Jr., Sloan, H. R., and Fredrickson, D. A.: Glycolipids and other lipid constituents of normal human liver. J. Lipid Res. 11:322, 1970. 8. Whipple, C. H., andBradford, W. L.: Racial or familial anemia of children as- For personal use on November 19, 2010.www.bloodjournal.orgFrom
  • 7. 462 ZAINO ET AL. sociated with fundamental disturbances of bone and pigment metabolism (Cooley-von Jaksch). Amer. J. Dis. Child. 44:336, 1962. 9. Astaldi, C., Rondanelli, E. C., Ber- nardelli, E., and Strosselli, E.: An abnor- mal substance in the erythroblasts of tha- lassemia major: Cytochemical investigations. Acta Haemat. (Basel) 12:145, 1954. 10. Sen Gupta, P. C., Chatterjea, A. M., Mukherjee, A. M., and Chatterji, A.: Ob- servations on the foam cell in thalassemia. Blood 16:1039, 1960. 11. Dameshek, W.: Thalassemia or what’s in a name. Blood 10:293, 1955. 12. Eto, T., Ichikawa, Y., Nishimura, K., Ando, S., and Yamakawa, T.: Chemistry of lipids of the posthemolytic residue or stroma of erythrocytes. J. Biochem. (Tokyo) 64: 205, 1968. 13. Jordan, S. W.: Electron microscopy of Gaucher cells. Exp. Molec. Path. 3:76, 1964. 14. Hibbs, R. C., Ferrans, V. J., Cip- riano, P. R., and Tardiff, K.J.: A histo- chemical and electron microscopic study of Caucher cells. Arch. Path. (Chicago) 89: 137, 1970. 15. Lee, R. E., Balcezak, S. P., and Westerman, M. P.: Gaucher’s disease. Amer. J. Med. 42:891, 1967. 16. Pennelli, N., Scaravilli, F., and Zac- chello, F.: The morphogenesis ofCaucher cells investigated by electron microscopy. Blood 34:331, 1969. For personal use on November 19, 2010.www.bloodjournal.orgFrom