pected body effusions may be helpful in early diagnosis of either SLE or PSLE.
RAFAEL S. CAREL, MD MENACHEM S. SHAPIRO, MD OLINDA CORDOBA, MD ROMAMTI TARAGAN, MD ARON GUTMAN, MD Ramat-Gan, Israel
REFERENCES
1. Pandya MR, Agus B, Grady RF: In vivo LE phenomenon in pleural fluid. Arthritis Rheum 19:962-963, 1976
2. Carel RS, Shapiro MS, Shoham D, Gutman A: Lupus ery- thematosus cells in pleural effusion. Chest 72:670-672, 1977
3. Weinstein J: Hypocomplementemia in hydralazine-associ- ated systemic lupus erythematosus. Am J Med 65:553-556, 1978
Adrenocortical carcinoma in a patient with systemic lupus erythematosus treated with azathioprine
To the Editor:
We have observed the development of a rare ma- lignancy, adrenocortical carcinoma, in a patient with systemic lupus erythematosus (SLE) who was treated with azathioprine. Adrenocortical carcinoma in a pa- tient with SLE has not been described previously, nor has the presence of this malignancy in a patient receiv- ing azathioprine.
FP, a 47-year-old white male, was referred to the Brooklyn Veterans Administration Medical Center in June 1977 with a 4-week history of left flank pain, 4.5 kg weight loss, and fever. SLE had been diagnosed in 1959 at the time of the onset of arthritis and a positive LE cell test. Over the succeeding years, he had multiple manifestations of SLE including deforming arthritis, pleural and pericardial effusions, grand mal seizures, hemolytic anemia, and proteinuria. Eventually he ful- filled 6 of the 14 American Rheumatism Association criteria for SLE (1). Prednisone (up to a maximum dose of 40 mg/day) was initiated in 1962. Azathioprine 100 mg three times a day was begun in 1974. From that time until admission he received the azathioprine, predni- sone 10 mg every other day, diphenylhydantoin sodium 300 mg/day, and phenobarbital 30 mg/day.
On physical examination the patient appeared chronically ill. Blood pressure was 100/70 mm/Hg, pulse 100/minute, respirations 16/minute, and temper-
ature was 38.5℃. There were no stigmata of Cushing’s syndrome. Tenderness and fullness were present in the left flank, and the spleen and liver were palpated at the costal margins. Proximal muscle weakness was found in all extremities. Results of the remainder of the examina- tion were normal.
Laboratory studies showed a hemoglobin of 8.9 gm%, hematocrit of 26%, and white blood count of 16,800 cells/mm3 with 84% polymorphonuclear leuko- cytes. Urinalysis was normal. Blood urea nitrogen was 38 mg% and serum creatinine was 2.5 mg%. Serum alka- line phosphatase, lactic dehydrogenase, and leucine- aminopeptidase levels were elevated. Antinuclear anti- body and LE tests were negative at this time; serum complement levels were normal. Plasma cortisol levels were normal but did not suppress after 48-hour admin- istration of 2 or 8 mg/day of dexamethasone. Chest x- ray and skeletal survey were normal. Sonography and angiography revealed a left solid suprarenal mass with cystic areas. Liver, spleen, and bone scans revealed no evidence of metastases.
At surgery, a 12 cm hemorrhagic tumor of the left adrenal gland was removed. Histologically, the tu- mor was an undifferentiated carcinoma of the adrenal cortex. One month after surgery, metastases to the skin, brain, and ribs became apparent. Despite therapy with 1,1 dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) eth- ane, the patient’s condition deteriorated. A right upper lobe pulmonary infiltrate appeared, respiratory in- sufficiency and hypotension developed, and the patient died. Autopsy permission was denied.
Adrenocortical carcinoma has not been reported previously in either SLE or in patients receiving azathioprine. In a study of 484 patients with SLE, a higher incidence of cancer (3.7%) was found than in a control population (2). Only 1 of 18 patients developing malignancy had received an immunosuppressive drug other than corticosteroids. The malignancies seen did not differ in type from those occurring in the control group. Another review of 70 patients with SLE reported an 11.4% incidence of malignancy (3). Three-quarters of these patients had been treated with immuno- suppressive agents. Azathioprine has been implicated in the 5% incidence of cancer in patients with renal trans- plants (4). Both the size of the azathioprine dose (300 mg/day in a man weighing 65 kilograms) and the dura- tion of azathioprine therapy (3 years) were exceptional in the patient reported here. It is not possible to be cer- tain of the contribution of azathioprine to the develop- ment of this patient’s adrenocortical cancer, however
the increased incidence of malignancy in SLE with and without immunosuppressive drug treatment warrants close observation of these patients for tumor develop- ment.
ELEANOR Z. WALLACE, MD PAUL M. ROSMAN, DO ADRIANA BALTHAZAR, MD ALAN SACERDOTE, MD Medical Service Brooklyn VA Medical Center Brooklyn, NY 11209
Department of Medicine Downstate Medical Center State University of New York Brooklyn NY 11203
REFERENCES
1. Cohen AS, Reynolds WE, Franklin EC, et al: Preliminary criteria for the classification of systemic lupus erythema- tosus. Bull Rheum Dis 21:643-648, 1971
2. Lewis RB, Castor CW, Knisley RE, Bole GG: Frequency of neoplasia in systemic lupus erythematosus and rheuma- toid arthritis. Arthritis Rheum 19:1256-1260, 1976
3. Canoso JJ, Cohen AS: Malignancy in a series of 70 patients with systemic lupus erythematosus. Arthritis Rheum 17:383-388, 1974
4. Penn I, Starzl TE: Immunosuppression and cancer. Trans- plant Proc 5:943-947, 1973
Influence of cytotoxic agents on the development of lymphoid neoplasms in connective tissue diseases
To the Editor:
We recently reviewed 29 patients seen at the Mayo Clinic from 1965 through 1975 who developed a lymphoid neoplasm following an established connective tissue disease (1). In this group there were 19 patients with rheumatoid arthritis, 4 with psoriatic arthritis, 2 with Sjögren’s syndrome, 2 with scleroderma, 1 with systemic lupus erythematosus, and 1 with ankylosing spondylitis. Of the 29 patients studied, 12 had malig- nant lymphoma with diffuse large cell morphology, one of which was an immunoblastic cell type, 6 had lym- phocytic lymphomas, 2 had Hodgkin’s disease, 3 had plasma cell myelomas, and 6 had chronic lymphocytic leukemia.
In this group of 29 cases, 2 patients were receiv- ing agents which might be suspected of inducing on- cogenesis. One patient had ankylosing spondylitis and
at age 21 was treated with x-ray therapy to the spine. Fifteen years later he developed a lymphoma involving the stomach and bone. The other patient who had pso- riatic arthritis had been treated with methotrexate for 1 year, and 4 years later the patient developed Hodgkin’s disease. None of the 29 patients had taken azathioprine or cyclophosphamide prior to the development of the lymphoid neoplasm.
There have been reports of neoplasms occurring in patients with connective tissue diseases. Lymphoid neoplasms and multiple myeloma have been reported in patients with rheumatoid arthritis; however we do not know if the incidence of these neoplasms is actually in- creased in this population (2,3). Neoplasms and particu- larly carcinomas are apparently more frequent in pa- tients with systemic lupus erythematosus (3). There is an increased frequency of lymphoid neoplasms in pa- tients with Sjögren’s syndrome (4). In these reports the induction of the neoplasms may have been influenced in some cases by the prior use of cytotoxic agents.
There have been case reports of the development of neoplasms, including lymphomas, leukemias, and carcinomas, in patients with connective tissue diseases following the use of cytotoxic agents (5,6). However, in our patients we cannot implicate the use of cyclophos- phamide or azathioprine in the development of the lym- phoid neoplasms.
DOYT L. CONN, MD PETER M. BANKS, MD GEOFFREY A. WITRAK, MD Mayo Clinic 200 First Street, SW Rochester, Minnesota 55901
REFERENCES
1. Banks PM, Witrak GA, Conn DL: Lymphoid neoplasia following connective tissue diseases. Mayo Clin Proc 54:104-108, 1979
2. Zawadski ZA, Benedek TG: Rheumatoid arthritis, dys- proteinemic arthropathy, and paraproteinemia. Arthritis Rheum 12:555-568, 1979
3. Lewis RB, Castor CW, Knisley RE, Bole GG: Frequency of neoplasia in systemic lupus erythematosus and rheuma- toid arthritis. Arthritis Rheum 19:1256-1260, 1976
4. Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R, Kimberly RP, Budman DR, Costa J, Decker JL, Chused TM: Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89:888-892, 1978
5. Alexson E, Brandt KD: Acute leukemia after azathioprine treatment of connective tissue disease. Am J Med Sci 273:335-340, 1977