1971 38: 457-462    

 EDWARD C. ZAINO, MARIO B. ROSSI, TUAN DUC PHAM and HENRY A. AZAR  

Gaucher’s Cells in Thalassemia

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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 cells are de-

scribed in the spleen and bone marrow

of patient with thalassemia major, by

light and electron microscopy. The ultra-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 that the

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 it is presumed to be due to excessive granulo-

cytic turnover.3#{176}

Fig. 1.-Aspirated bonemarrow. 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 i\Iedical Center, Kansas City, Kan.s.; formerly Associate

Professor of Pathology, Francis Delafield Hospital, Columbia University School of Medicine,

New York, NY.

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458 ZAINO ET AL.

Fig. 2.-Aspirated bone

marrow, showing faint out-lines of the phagocytizedervthrocyte. x 1200.

\Ve are reporting the presence of Gaucher or Gaucher-like cells 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 at the age of 43� years; at that time she had

moderate hepatosplenomegaly. The patient had never had a blood transfusion prior to the

hospital admission. She complained of frontal headaches, palpitations, tiredness, and short-ness of breath. On physical examination she was small in size. There was pallor, scleralicterus, bossing of the parietal l)ones and prominence of the zygoma. The liver and spleenwere enlarged; the liver was 4 cm and the spleen 8 cm below the costal margin. There

was cardiac enlargement with a grade 4/6 systolic murmur, and a hepatojugular reflux.

Fig. 3.-PAS-positivecells in tile spleen. X 320.

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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 showedhypochromia, target cells, anisocytosis, poikolocytosis, basophilic stippling, and nOrfllOblasts.She had a fetal hemoglobin of 75%, increased A2 hemoglobin (8%), decreased fragility tosaline, a bilirubin of 4.0 mg, mainly indirect, and normal BUN, calcium, total protein,

alkaline phosphatase, and SCOT. X rays of the skull showed osteoporosis and characteristic“hair on end” appearance. The aspirated bone marrow, smears and sections, were verycellular, 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). Thesecells 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

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Fig. 5.-(A) Tubular structures that vary in density as �vell as configuration. X

13,500. (B) Higher magnification of tile membrane-bound tubular structures and

mitochondria. X 51,000.

460 ZAINO ET AL.

moderate-sized tubules in the 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 transfusions 13 mo after the

splenectomy.

MATEmALS AND METHODS

Part of the bone marrow and tissue samples from the spleen were fixed 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 fixed in 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 then with ethyl acetate. Acetone then completely removed all themono-, di-, and trihexosvl ceramides from the column. Following alkaline methanolysis, the

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GAUCHER’S CELLS IN THALASSEML� 461

glycolipids were separated by Silica gel C thin-layer chromatography and quantitated by

gas chromatography.7

DIsc�ussIoN

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 in this 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 we are 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 Lung Institute, 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 ofa defict�ncy of glucocerebroside-cleavingenzyme in Caucher’s disease. J. Clin. Invest.45:1112, 1966.

3. Smith, W. C., Kaneshiro, M. M.,Goldstein, B. D., Parker, J. W., and Lukes,R. J.: Gaucher cells in chronic granulocyticleukemia. 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.: Gauchercells in leukemia. JAMA 209:935, 1969.

6. Gerdes, J., Marathe, R. L., Bloodworth,M. B., and MacKinney, A. A.: Cauchercells in chronic granulocytic leukemia. Arch.Path. (Chicago) 88:194, 1969.

7. Kwiterovich, P. 0., Jr., Sloan, H. R.,and Fredrickson, D. A.: Glycolipids andother lipid constituents of normal humanliver. J. Lipid Res. 11:322, 1970.

8. Whipple, C. H., and Bradford, W. L.:Racial or familial anemia of children as-

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462 ZAINO ET AL.

sociated with fundamental disturbances ofbone and pigment metabolism (Cooley-vonJaksch). 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’sin a name. Blood 10:293, 1955.

12. Eto, T., Ichikawa, Y., Nishimura, K.,

Ando, S., and Yamakawa, T.: Chemistry oflipids of the posthemolytic residue or stroma

of erythrocytes. J. Biochem. (Tokyo) 64:205, 1968.

13. Jordan, S. W.: Electron microscopyof 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 ofCaucher cells. Arch. Path. (Chicago) 89:

137, 1970.

15. Lee, R. E., Balcezak, S. P., andWesterman, M. P.: Gaucher’s disease. Amer.

J. Med. 42:891, 1967.16. Pennelli, N., Scaravilli, F., and Zac-

chello, F.: The morphogenesis of Caucher

cells investigated by electron microscopy.

Blood 34:331, 1969.

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