Gaucher 's Disease and Chronic Lymphocytic Leukemia

Possible Pathogenetic Link Between Gaucher 's Disease and B-Cell Proliferations?

HENRY FOX, MD, PHILIP MCCARTHY, MD,* JANINE ANDRE-SCHWARTZ, MD, YEHUDA SHOENFELD, MD, AND KENNETH 6. MILLER, MD

The authors report a case of Gaucher's disease with chronic lymphocytic leukemia. The diagnosis of Gaucher's disease was confirmed by electron microscopy and glucocerebrosidase assay. There may be a pathogenetic link between Gaucher's disease and B-cell proliferation.

Cancer 54:312-314, 1984.

ASES OF GAUCHER'S DISEASE have been reported in C association with both benign and malignant B-cell disorders including diffuse hypergamrnaglobulinemia,'.* monoclonal garnm~pathies,~,~ and multiple mye- l ~ m a . ~ - ~ We present a patient with the combination of Gaucher's disease and chronic lymphocytic leukemia.

Two previous reports have suggested this a s soc ia t i~n .~~ '~ We have confirmed these findings with ultrastructural, immunochemical, and enzymatic studies. The possible linkage between these two disorders is discussed.

Case Report

A 7 1 -year-old white man of Eastern European Jewish ancestry presented with asymptomatic splenomegaly, lymphocytosis, and thrombocytopenia of 2 years' duration. Previous illnesses in- cluded peripheral vascular disease, hypertension, and gout. There was no family history of Gaucher's disease. Physical examination disclosed a normal liver span, and a spleen enlarged to 10 cm below the left costal margin. No peripheral lymphadenopathy was detected. Laboratory results included hemoglobin 1 3.9 g/dl; hematocrit 40.5%; leukocyte count 19,000/mm3 with a differential count of 91 lymphocytes and 9 neutrophils with occasional smudge cells; platelet count 5 1 ,000/mm3. Serum protein electrophoresis was normal. Bone marrow aspirate and biopsy showed greater than 90% replacement with lymphocytes mostly of small size, with some of moderate size. Occasional

Gaucher or Gaucher-like cells were noted. Cell surface markers revealed that 80% of the peripheral blood lymphoid cells were B-cells (IgM k) and that less than 1% formed erythrocyte (E)- rosettes. Tartrate-resistant-acid-phosphatase staining of the pe- ripheral blood mononuclear cells was negative. Electron mi- croscopic examination of the peripheral blood revealed, however, that 10% of the lymphocytes exhibited numerous microvilli or pseudopods (Fig. 1 ).

The patient remained free of symptoms 1 year later. Physical examination and laboratory findings were essentially unchanged. Splenectomy was advised, but the patient refused. One year later he developed recurrent hemorrhage from esophageal var- ices. Splenectomy was performed in an attempt to decompress the varices and to increase the platelet count. The patient did

From the Hematology-Oncology Division, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts.

Current address: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.

Address for reprints: Kenneth B. Miller, MD, New England Medical Center, 171 Harrison Avenue, Boston, MA 021 1 I .

The authors thank Dr. Harold Sanders, Dr. Ronald DeLellis, Dr. Robert S. Schwartz, Ms. Rita Antonelli, Ms. Margarett Baker and the Tufts University Educational Media Center for aiding in the research of the manuscript. FIG. 1. Patient's lymphocyte extending microvilli (thin arrows) and

Accepted for publication April IS, 1983. pseudopods (thick arrows) (X22,700).

312

No. 2 GAUCHER'S DISEASE AND CLL * F O X et d. 313

FIG. 2. Light micrograph of the spleen showing diffuse infiltration with small lymphocytes as well as numerous Gaucher or Gaucher-like cells (arrows) (X400).

well postoperatively. The platelet count returned to normal. The leukocyte count rose to 79, 100/mm3 with a differential of 88 lymphocytes, 10 neutrophils, and 2 eosinophils.

A presplenectomy bone marrow examination again showed a hypercellular marrow with a predominance of mature lym- phoid cells. At surgery, the spleen weighed 2520 g. Light mi- croscopic examination of the spleen disclosed lymphocytic in- filtration as well as numerous Gaucher or Gaucher-like cells (Fig. 2). These cells stained periodic acid-Schiff (PAS) positive. No de novo pseudosinuses were observed. A liver biopsy showed portal and focal sinusoidal infiltration by small lymphocytes but no hepatic angiomatous lesions; in addition, there were occasional Gaucher or Gaucher-like cells. Electron microscopic examination confirmed the light microscopic observations and detected a slight increase in the number of splenic histiocytes. More importantly, it revealed that the suspected Gaucher cells were typical for Gaucher's disease (Fig. 3). Glucocerebrosidase activity (assayed with fluorogenic substrate) of sonicated pe- ripheral blood leukocytes was 22% of normal, confirming the diagnosis of Gaucher's disease."

<12) with tartrate inhibited fraction of 4.7 U/1 (normal, c3.5). Immunoelectrophoresis was normal, and the total IgG level was

Other studies acid phosphatase I 1'4 u/l FIG. 3. EM of the spleen. A cluster of four Gaucher's cells (G) is Seen among lymphocytes (L) (original magnification X4000). Inset: Detail of tubular structures (original magnification X3 1,000).

314 CANCER July 15 1984 VOl. 54

normal at 16.1 mg/ml. Skin testing revealed that the patient was not anergic.

Discussion

The patient reported here presented with both a ma- lignant B-cell proliferation and Gaucher’s disease. The findings of splenomegaly with minimal lymphadenopathy, the presence of a few atypical peripheral blood lympho- cytes, and the slight increase in splenic histiocytes favor the diagnosis of hairy cell leukemia. However, the findings of leukocytosis, homogeneous infiltration of the spleen and the absence of pseudosinuses in that organ, and lack of angiomatous lesions in the liver make the diagnosis of chronic lymphocytic leukemia most likely. I 2

Gaucher-like cells have been described in a variety of hematologic disorders. By light microscopy, these cells are indistinguishable from the true Gaucher cells of Gaucher’s disease. Gaucher-like cells may be seen in my- eloproliferative disease’ and in hematologic malignancies of lymphocytic 0rigi11.l~ Since cellular turnover is high in most of these diseases, it has been postulated that phagocytes might become engorged by cellular debris, and thereby assume the appearance of Gaucher-like cells. Electron microscopic examination of such cells shows abundant heterogeneous inclusions. By contrast, ultra- structural observation of cells seen in Gaucher’s disease, as in the patient reported here, reveals cytoplasmic sacs containing tubular formations but no cell debris or dense bodies. These tubular formations have been shown to be aggregated glucocerebroside molecules contained within lysosomes. ’ ’ It is only recently that electron microscopic studies and specific enzyme assays have been used in conjunction to permit definite distinction between Gaucher’s disease and hematologic neoplasm with Gaucher-like cells.’5 This implies that earlier reports of the association of hematologic disorders and Gaucher’s disease (and conversely the presence of Gaucher-like cells in hematologic diseases) must be analyzed cautiously.

Several B-cell disorders have been reported in docu- mented primary Gaucher’s disease. These include hy- pergammaglobulinemia, 1,2 monoclonal gamm~pathies,~.~ and multiple rnye l~ma.~-~ Two previous cases of chronic lymphocytic leukemia in Gaucher’s disease have been reported’.’’; one was confirmed by glucocerebrosidase as- say, ’’ but neither included electron microscopic exami- nation to exclude Gaucher-like cells.

A pathogenetic link has been suggested between Gaucher’s disease and B-cell proliferation. Shoenfeld and associated6 found a correlation between the age of the patient and serum levels of immunoglobulins; these au- thors postulated that chronic stimulation of the immune system by accumulation of glucocerebroside could lead to benign or malignant B-cell proliferation. This mech- anism has been observed in mouse models. where chronic

exposure to various agents has resulted in B-cell malig- nancies.”

Two of the cases of multiple myeloma have been of the nonsecretory type.6.’6 Nonsecretory myeloma is rel- atively infrequent (4% of all myelomas). In the patient we report, the malignant cells were B-cells expressing IgM kappa light chains on their cell surfaces. There was no detectable monoclonal component on serum protein electrophoresis. This may represent an arrest in the de- velopment of the B-cell. A comparable mechanism may occur in nonsecretory myelomas. The mechanism re- sponsible for the maturation arrest is unclear, but could represent a defect in either the lymphoid or monocyte lineage. A monocyte defect, probably on the basis of de- creased glucocerebrosidase activity or accumulated glu- cocerebroside, could interfere with normal immunoreg- ulation.

REFERENCES

1. Shoenfeld Y, Berliner S, Pinkhas J et ul. The association of Gau- cher’s disease and dysproteinemias. Actu Huemutol (Busel) 1980 64:24 1- 243.

2. Pratt PW, Estren S, Kochwa S. Immunoglobulin abnormalities in Gaucher’s disease: Report of 16 cases. Blood 1968; 31:633-640.

3. Merlini G, Turesson I, Osserman EF. Monoclonal gammopathy associated with Gaucher’s disease. Budapest, Hungary. International Congress ISH/ISBT, 1982, 176.

4. Mane JP, Tulliez M, Tricotter-Paczinski V et ul. Gaucher’s disease and monoclonal gammopathy. Scund J Huernutol 1982; 2854-58.

5 . Miller W, Lamon JM, Tavassoli M et ul. Multiple myeloma com- plicating Gaucher’s disease (Specialty Conference). West J Med 1982;

6. Benjamin D, Joshua J, Djaldetti M et ul. Nonsecretory IgG kappa multiple myeloma in a patient with Gaucher’s disease. Scund J Huemutol

7. Ruestow PL, Levinson DJ, Catchatourian R et ul. Coexistence of IgA myeloma and Gaucher’s disease. Arch Intern Med 1980; 140:1115- 11 16.

8. Garfinkel D, Sidi Y, Ben-Bassat M ei ul. Coexistence of Gaucher’s disease and multiple myeloma. Arch Intern Med 1982; 142:2229-2230.

9. Chang-Lo M, Yam LT, Rubenstone A1 et ul. Gaucher’s disease associated with chronic lymphocytic leukemia, gout and carcinoma. J Puthol 1975; 116:203-207.

10. Mark T, Dominguez C, Rywlin AM. Gaucher’s disease associated with chronic lymphocytic leukemia. South Med J 1982; 75:361-363.

11. Peters SP, Clew RH, Lee RE. Gaucher’s disease: Practical en- zymology of the sphingolipidoses. In: Glew RH, Peters SP, eds. Lab- oratory and Research Methods in Biology and Medicine, vol. 1. New York: Alan R. Liss, 1977; 71-100.

12. Nanba K, Soban EJ, Bowling MC et ul. Splenic pseudosinuses and hepatic angiomatous lesions: Distinctive features of hairy cell leu- kemia. Am J Clin Puthol 1977; 67:415-426.

13. Takahashi K, Terashima K, Kojima M et ul. Pathological, his- tochemical and ultrastructural studies on sea-blue histiocytes and Gaucher-like cells in acquired lipidosis occurring in leukemia. Actu Puthol Jpn 1917; 27:715-797.

14. Scullin DC, Shelbourne JD, Cohen HJ. Pseudo Gaucher cells in multiple myeloma. Am J Med 1979; 67:347-351.

15. Lee RH, Clew RH. Gaucher’s disease: Clinical, morphological and pathological considerations. Puthol Annu 1977; 12:309-339.

16. Shoenfeld Y, Gallant LA, Shaklai M et a/. Gaucher’s disease: A disease with chronic stimulation of the immune system. Arch Puthol Lab Med 1982; 106:388-391.

17. Potter M, Boyce CR. Induction of plasma cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants. Nature 1962; 193: 1086-1087.

1361122-128.

1979; 22:179-184.