Gaucher's disease associated with Hodgkin's disease

Gaucher’s DiseaseAssociated with Hodgkin’s Disease

ALEX H. BRUCKSTEIN, M.D.* ARTHUR KARANAS, M.D. JOHN J. DiRE, M.D. New York,New York

A patient with chronic adult-onset Gaucher’sdisease is described. The diagnosis was based on the finding of typical Gaucher cells in the spleen, liver and bone marrow ailsociatedwith deficiency of glucocerebrosidase.The patient also had Hodgkin’sdisease, noduIar sclerosis type, stage III. The patient is alive and relatively well six years after presentation, having been treated with a combination of chemotherapeutic regimens. Previously reported cases of Garicher’sdisease concurrent with Hodgkin’sdisease are reviewed. Gaucher’s disease is an autosomal recessive disorder characterized by a deficiency of glucocerebrosidase, the enzyme that catalyzes cleavage of glucose from glucosyl ceramide. The enzymatic deficiency results in accumulation of glucosyl ceramide in reticuloendothelial cells. This deficit is the basis for the principal clinical features of Gaucher’s disease: bone marrow infiltration, splenomegaly, hepatomegaly and, occasionally, lymphadenopathy. Secondary hypersplenism often occurs, and the resulting thrombocytopenia, anemia and leukopenia may require splenectomy. A common manifestation is osseous involvement which may cause pain, aseptic necrosis and pathologic fractures (I]. Neoplasia associated with Gaucher’s disease is rare and has been reported in only a few instances [2-151. There are three reports of Hodgkin’sdisease in patients whose histologicfindings were consistent with Gaucher’s disease [2-41. We report a fourth case of Hodgkin’s disease and enzyme-proved Gaucher’s disease in a patient who has been under treatment for Hodgkin’s disease for six years. The occurrence of the two disorders is reviewed. CASE REPORT

From the Department of Medicine and Pathology, The Roosevelt Hospital and the College of Physicians And Surgeons, Columbia University, New York, New York. Requests for reprints should be addressed to Dr.’ Arthur Karanas, Roosevelt Hospital, 428 West 59th Street, New York, New York 10019. Manuscript accepted June 29,1979. ‘* Present address: Gastroenterology Section, Veterans Administration Medical Center, New York, New York 10010.

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This previously healthy 23 year old man of Eastern European Jewish ancestry presented himself in 1972 with a three-month history of nontender right anterior cervical lymph node enlargement. Family history was negative except for a sister known to have systemic lupus erythematosus. Physical examination revealed bilateral anterior cervical lymphadenopathy and splenomegaly. Initial laboratory values were as follows: hemoglobin level 11.5 g/100ml, hematocrit value 34 per cent, platelet count 116,000/mm3, reticulocyte count 1.4 per cent. Leukocyte count was 6,100/mm3 with a differential count showing 71 per cent neutrophils, 4 per cent eosinophils, 23 per cent lymphocytes and 2 per cent monocytes. A biopsy specimen of a cervical lymph node was interpreted as Hodgkin’s disease, nodular sclerosis type. The patient underwent staging laparotomy and splenectomy. Hodgkin’s disease and numerous Gaucher cells

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F&e 1. Spleen with Gaucher’s disease and focus of Hodgkin’s disease of the nodular sclerosis type. Inset left shows the Gaucher cells in detail; inset right shows typical Reed-Sternberg cells. Hematoxylin and eosin stain, magnification X 35 and X 400. (insets X 400).

were found to coexist in the spleen (see Figure 1).Gaucher cells were also found in the liver. Hodgkin’s disease, nodular sclerosis type, was found in the para-aortic, splenic hilar, and splenic flexure nodes. Bone marrow aspiration and biopsy revealed Gaucher cells but not Hodgkin’s disease. Serum acid phosphatase was 5.8 Bodansky units (normal, less than 0.8 Bodansky units). Bone survey disclosed no abnormalities except for a lucent defect in the distal right femur. Assay of glucocerebrosidase [16]in fibroblast cultures from skin was kindly performed by Dr. Harold Nitowsky, Albert Einstein College of Medicine. The patient’s value was 3.6 mmol of 4-methylumbeIliferyl/mg protein/min; that in his mother 24.3 mmol4-methylumbelliferyl/mg protein/min. (2.9 to 7.9 mmol is the range of activity for patients with Gaucher’s disease; 35 to 45 mmol is considered normal). The patient was treated with six courses of MOPP (mechlorethamine hydrochloride, vincristine, procarbazine and prednisone) therapy for the next six months, during which all observable lymphadenopathy completely disappeared. A month later, he had a nonproductive cough, fever, dyspnea and infiltrates in the lower lobes of both lungs. Open lung biopsy revealed Pneumocystis carinii pneumonitis. The patient was treated with pentamidine isethionate with rapid and complete resolution of the pulmonary infiltrate. His subsequent course has consisted of recurrent lymphadenopathy and fever which have responded to vinblastine, thiotepa and bleomycin therapy. Repeat lymph node biopsies 20 months after onset, and 10 months later, again showed Hodgkin’s disease, nodular sclerosis type, and not Gaucher’s disease. Repeat bone marrow examinations have revealed

marked replacement of normal elements with Gaucher cells but not with Hodgkin’s disease. COMMENTS

The diagnosis of Gaucher’s disease has traditionally been established by demonstrating organ infiltration with the typical glucosyl ceramide-laden storage cells first described by Gaucher in 1882 [17]. The serum acid phosphatase level, measured with the use of phenyl phosphate as substrate, is usually elevated. I? 1965, Brady et al. [38,19] demonstrated the basic defect in Gaucher’s disease to be a genetically determined deficiency of the enzyme glucocerebrosidase. A deficiency of this enzyme results in the accumulation of glucocerebroside in storage cells. The enzyme deficiency can be detected in liver, spleen, brain, leukocytes and skin fibroblasts [l]. A partial deficiency can be shown in both carrier parents of an affected subject: the parents have enzymatic activity intermediate between the normal level and that found in patients. In 1969, Kattlove et al. [S] reported “Gaucher-like” cells in a patient with chronic granulocytic leukemia. Morphologically, these cells were indistinguishable from those seen in the genetic disorder. This patient’s leukocytes, however, had an elevated rather than a reduced level of glucocerebrosidase. It was postulated that the increased activity was induced by overproduction of glucocerebroside caused by a markedly increased granulocyte turnover. The increased enzyme activity,

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TABLE I

DISEASE-BRLJCKSTEIN

ET AL.

Clinical Aspects of Patients with Gaucher’s Dlsease Associated with Hodgkin’s Disease Reference Sharer et al. [2]

Gaucher’s disease Age at diagnosis (yr) Presentation Complications

Hodgkin’s disease Age at diagnosis (yr) Presentation

Cellularity Laparotomy Hodgkin’s disease

Gaucher’s disease

7 Aseptic necrosis of femoral heads Bleeding secondary to thrombocytopenia, treated with splenectomy at age 19

7

5

Splenectomy

28 Generalized herpes zoster, left cervical adenopathy Lymphocyte predominance

27 Fever, chills, left cervical adenopathy

27 Axillary adenopathy

Right para-aotiic stage IIIA

Liver, stage IVB

Bone marrow, stage IVB

Pelvic and para-aortic nodes, bone marrow .

Bone marrow

nodes,

.

at age 5

Mixed cellularity

l

.

MOPP and bleomycin Ascites, gram-negative

l

sepsis 31

.

Portahepatis, paraaortic and carinal nodes, liver

Gaucher’s disease

l

*

28

Age at death (yr) Autopsy Hodgkin’s disease

Liver, bone marrow, pancreas, stomach, duodenum, jejunum. ileum, mesentery, sympathetic trunk, and mediastinal, cervical and retroperltoneal nodes Mediastinal, cervical, retroperitoneal nodes, liver, lung

.

Portahepatis, paraaortic and axillaty nodes, liver

Bruckstein et al.

17 Incidental finding

l

Knee pain

Radiotherapy Fever, anemia

Therapy Complications

Cho, Sastre [4]

Bleeding secondary to thrombocytopenia, treated with splenectomy at age 18 aseptic necrosis of hips

All abdominal nodes, liver, bone marrow Elevated acid phosphatase level

Enzymes

Katzen [3]

None

17 Bilateral cervical adenopathy, splenomegaly Nodular sclerosis

Bilateral cervical, splenic hitar and splenic flexure nodes, spleen, stage IIIA Spleen, liver and bone marrow Elevated acid phosphatase level and decreased glucocerebrosidase MOPP Pneumocystis carinii pneumonitis, anemia and thrombocytopenla Alive at 23

...

Information not available.

however, was presumably insufficient to metabolize the excess substrate, and glucocerebroside accumulated in reticuloendothelial cells. In contrast, the tissue level of glucocerebrosidase is markedly reduced in true Gaucher’s disease and glucocerebroside accumulation results from insufficient enzyme to metabolize a normal amount of substrate. Neoplasia associated with Gaucher’s disease is uncommon and has been reported in only a few instances. Review of the literature reveals only three cases of Hodgkin’s disease associated with Gaucher’s disease but in none was the enzyme deficiency verified. Gaucher’s disease or “Gaucher-like” cells have been reported in association with acute [5] and chronic [6-91 myelogenous leukemia, acute [5;9] and chronic[lO] lymphocytic

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leukemia, multiple myeloma [ll] and monoclonal gammopathy [l&13], all diseases of hematopoietic origin. Most of these diseases are characterized by increased destruction of blood cells. “Gaucher-like” cells have also been reported in the bone marrow associated with cerebral astrocytoma [l4] and with bronchogenic carcinoma 1151. To distinguish between true Gaucher’s disease and “Gaucher-like” cells accompanying other diseases, measurement of the enzyme glucocerebrosidase must be made. The finding of decreased amounts of this enzyme in the patient described herein confirms the presence of true Gaucher’s disease coexisting with Hodgkin’s disease. All three previously described patients, and our patient, presented themselves with extensive Hodgkin’s

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disease as determined by clinical and pathologic staging (see Table I). Two patients had stage III disease, and two had stage IV disease as ascertained by a positive liver biopsy in one and a positive marrow biopsy in the second. Histology varied among lymphocyte predominance, nodular sclerosis and mixed cellularity. The treatment of choice for Hodgkin’s disease complicated by Gaucher’s disease is not known. Hematopoietic toxicity is a major consideration because of the extensive infiltration of the bone marrow with Gaucher cells. The patient de%ribed by Sharer et al. [2] (stage III, lymphocyte predominance] was treated with radiotherapy (2,000rads to a mantle port, 2,000 rads to a pelvic port, 2,500 rads to the para-aortic and splenic pedicle areas, and 750 rads to both inguinal-femoral areas over a three month period) followed by a modified MOPP protocol. The patient succumbed to hemorrhage from peptic ulcer disease within one year while he was thrombocytopenic and receiving prednisone. Extensive Hodgkin’s disease was present at autopsy. The patient described by Cho and Sastre [a] (stage IV, mixed cellularity) and our patient (stage’ III, nodular sclerosis] were both treated with chemotherapy alone. The former lived four years and died of massive hemorrhage from ulcerated gastric Hodgkin’s disease while he was thrombocytopenic and receiving prednisone. Our patient is still alive at six years, attending college and leading a relatively normal existence. He is presently being treated with a combination of vinblastine, thiotepa and bleomycin. It has been questioned whether splenectomy in Gaucher’s disease predisposes to Hodgkin’s disease [4]

ET AL.

and also causes premature or accelerated bone disease by removing a large reservoir for glucosyl ceramide [ZO]. The simultaneous occurrence of both diseases in our patient suggests that spleneytomy has no causal relationship to the development of the Hodgkin’s disease. In three of the four cases (see Table I), osseous manifestations preceded splenectomy and did not appear to be accelerated. It is not known whether Gaucher’s disease influences the natural history, treatment or survival of patients with Hodgkin’s disease. Extent of disease, histology and age at onset are known to be important prognostic factors in Hodgkin’s disease. Gaucher’s disease may have no influence on the behavior of the other disease. However, one might suppose that splenic sequestration and marrow replacement could limit effective therapy of the lymphoma. From the limited data available, it appears that chemotherapy of Hodgkin’s disease in previously splenectomized patients is tolerated and compatible with a survival time of several years. Patients with Gaucher’s disease, however, may not tolerate more intensive regimens such as combination radio- and chemotherapy. Drug combinations that include bleomycin may be particularly beneficial because this drug does not cause hematopoietic toxicity. It is to be hoped that enzyme replacement [21] becomes a feasible method of correcting the deficiency in Gaucher’s disease. Such a therapeutic benefit would be particularly desirable in patients with the disease occurring in association with other hematopoietic disorders in whom toxic chemotherapeutic regimens are required.

REFERENCES 1.

Fredrickson DS, Sloan HR: Glucosyl ceramide lipidoses: Gaucher’sdisease, chaD33. The Metabolic Basisof Inherited Disease. 3rd ed., edited by Stanbury IB, Wyngaarden JB. Fredrickson DS. New York: McGraw Hill, 1972; 730-759.

2.

3. 4. 5. 6. 7.

8. 9.

10.

11.

Sharer LR. Barondess]A, Silver RT, Gray GF: Association of HodgkinDiseaseand gaucherdisease.ArchPath011974; 9R~376-37R _-. _. _ _. _. KatzenBT:Positivelymphangiographyin Gaucher’s disease.

Radiology 1975; 115: 85-86. Cho SY. Sastre N: Coexistence of hodekin’s disease and gauch&‘s disease. Am J Clin Path01 1&‘6: 65: 103-108. Gelfand MI, Griboff SI: Gaucher’s disease and acute leukemia. J Mt Sinai Hosp NY 1961; 28: 278-282. Albrecht VM: “Gaucher-zellen” b ei chronisch myeloischer leukamie. Blut 1966; 13: 169-179. Smith WC, Kaneshiro MM, Goldstein BD, Parket JW, Lukes RT: Gaucher cells in chronic granulocytic leukemia. Lancet 1968; 2: 780-781. Kattlove HE, Williams JC, Gaynor E. Spivack M, Bradley RM, Bradv RO: Gaucher cells in chronic mvelocvtic leukemia: an acquired abnormality. Blood 1969;33: 3?9-399. Rosner F. Dasik H, Kaiser SS. Lee SL, Morrison AN: Gaucher cells in leukemia. JAMA 1969; 209: 935-937. Chang-Lo M. Yam LT. Rubenstone AI: Gaucher’s disease: review of the literature and report of twelve new cases. Am J Med Sci 1967; 254: 303-315. Pinkhas J, DJaldetti M. Yaron M: Coincidence of multipli myeloma with gaucher’s disease. Israel J Med Sci 1965; 1:

537-540. 12.

Wolf P: Monoclonal gammopathy in gaucher’s disease. Lab Med 1973; 4: 28. 13. Turesson I, Rausing A: Gaucher’s disease and benign monoclonal gammopathy. Acta Med Stand 1975; 197: 507512. 14. Davis M, Dorfman J: Gaucher’s disease associated with a cerebral astrocytoma. Am Practit 1961; 12:673-677. 15. Tsung SW, Cotes E: Coexistence of bronchogenic carcinoma and gaucher disease. Arch Path01 Lab Med 1977: 101: 56. 16. Ho MW, Seek J, Schmidt D, et al.: Adult gaucher’s disease: kindred studies and demonstration of a deficiency of acid beta-glucosidase in cultured fibroblasts. Am J Hum Genet 1972; 24: 37-45.

17.

Gaucher P: De l’epithelioma primitif de la rate. These de Paris. 1882. 18. Brady RO, Kanfer JN, Shapiro D: Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun 1965; 18: 221. 19. Brady RO, Kanfer JN, Bradley RM, Shapiro D: Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher’s disease. J Clin Invest 19% 45: 1132-1115. 20. Wilverstein MN, Kelly PJ: Osteoarticular manifestations of gaucher’s disease. Am J Med Sci 1967; 253: 569-577. 21. Belchetz PE, Crawley JCW, Braidman IP, Gregoriadis G: Treatment of gaucher’s disease with liposome-entrapped glucocerebroside-beta-glucosidase. Lancet 1977: 2: 116117.

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