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Multiple dermatofibromas in a patient with myasthenia gravis treated with prednisone and cyclophosphamide
Multiple dermatofibromas in a patie~t with myasthenia gravis treated with prednisone and cyclophosphamide Howard B. Bargman, M.D., and Irving Fefferman, M.D. Toronto and Scarborough, Ontario, Canada A middle-aged man developed multiple dermatofibromas on the legs and arms. The lesions were about sixty in number and were unusual in their rapid onset, their larger-than-average size, and their appearance in large numbers on the arms and trunk. They started approximately 4 months after the patient had begun a regimen of prednisone and cyclophosphamide for myasthenia gravis. This appears to be the second report of the development of multiple dermatofibromas in patients with an autoimmune disease that was being treated with immunosuppressive medications. (J AM ACAD DERMATOL 14: 351-352, 1986.)
Denrtatofibromas are common, benign intradermal nodules that appear to be more common in worrien. T~e cause is unknown, although a viral infection has been suggested. I They are known by several other names, including histiocytoma, nodular subepidermal fibrosis, and sclerosing hemarigioma. We wish to report the case of a middleaged man who developed numerous dermatofibromas following a diagnosis of myasthenia gravis and treatment with immuosuppressive medications. CASE REPORT The patient is a 53-year-old businessman who was well until January, 1979, when he presented to his family physician with a week's history of increasing muscle weakness brought on by exercise. The weakness especially involved the neck, eyelids, and shoulder girdle muscles. By the end of a game of racquetball, the patient would literally have to support his head with his hands. Referral was made to a neurologist, who confirmed the suspicion of myasthenia gravis by administering a From the Sunnybrook Medical Center, and Scarborough General Hospital. Reprint requests to: Dr. Howard Bargman, 2927 Lawrence Ave. E, Scarborough, Ontario M1P 2T5, Canada.
tensilon test with strongly positive results. At that time, the results of thyroid tests, blood urea rlitrogen tests, aspartate aminotransferase determination, antinuclear antibody tests, protein electrophoresis, and hemoglobin tests were all within normal limits. An x-ray of the chest did not suggest the presence of thymoma. Electromyogram showed typical responses suggestive of myasthenia gravis. The patient was started on a regimen of neostigmine six times a day, and his symptoms improved. No abnormalities of the skin were ever noted during this period. The patient was seen next in April, 1980, by another physician, who started him on prednisone, 100 mg/day, for systemic effect. A poor response prompted further search for thymoma, which was subsequently discovered and then surgically removed. The prednisone dose was reduced to 100 mg every either day, and cyclophosphamide, 50 mg/day, was begun and subsequently continued for 18 months. Pyridostigmine bromide (Mestinon) and epinephrine were given for short periods. Approximately 4 months after starting the cyclophosphamide, the patient noted the onset of skin growths that were firm, hyperpigmented, and asymptomatic. They continued to app~ar and to increase in size for many months. Dermatologic consultation was sought, and apparently the lumps were dismissed. It is not known whether a diagnosis was established at that time.
351
Journal of the American Academy of Dermatology
352 Bargman and Fefferman
Fig. 1. Medial aspect of the right thigh and leg, showing
multiple pigmented dennatofibromas. The lesions are larger than those which tend to be found in the nonnal individual.
All medications have now been discontinued for the last 2 years, and the patient feels completely well. There has been no change in the lesions since the medication was stopped. He is active in both business and sports, and in fact it was not until he played tennis with one of the authors (H. B. B.) that any interest in his skin was generated. Examination of the skin revealed approximately fifty to seventy finn, hyperpigmented intracutaneous nodules scattered over the legs (Fig. 1), anns, and trunk. These lesions measured as large as 1.3 em in diameter. Biopsy of a lesion from the left leg revealed the typical histologic picture of dennatofibroma.
DISCUSSION
Myasthenia gravis is a relatively uncommon disease of the neuromuscular junction. An autoimmune process is suspected because it is frequently associated with thyroid abnormalities and/or thymoma. It frequently improves after the thymoma is treated either by surgery or by x-ray therapy. Immunosuppressive drugs are sometimes beneficial, and in this case prednisone and cyclophosphamide were given. Dermatofibromas are common benign tumors of the skin and are probably seen daily in any busy dermatologic practice. They are few in number, tend to be less than 5 mm in diameter, and usually occur only on the legs, although they can be seen on the trunk and the arms. What is interesting in this case is the fact that the dermatofibromas began shortly after cyclosphosphamide was added to the
treatment schedule. Such a finding is not without precedent. Newman and Walter l reported four cases of multiple dennatofibromas in four women with systemic lupus erythematosus who had been receiving immunosuppressive therapy consisting of prednisone, azathioprine, or both. The lesions were not as numerous as in our case, and their size appeared to fall within nonnal range. The histologic picture of these dermatofibromas did not differ from that of the typical solitary kind. * Multiple dermatofibromas (greater than fifteen in number) in a normal patient are rare. Baraf and Shapir02 report a case of a 39-year-old woman with sixty-one lesions varying in size from 3 to 10 mm and were able to document only four previously reported cases. Their patient was healthy, but of the other four patients, one had diabetes and hydronephrosis and another had hypercholesterolemia and glycosuria. Winklemann and Muller reported on generalized eruptive histiocytoma and referred to four other reports. In this condition, healthy adults develop generalized symmetric, discrete, flesh-colored to bluish-red papules with no tendency toward grouping. The process "seems more closely related to the first histiocytic stage of nevoxanthoendothelioma than to the classic solitary dermatofibromas. "3 Multiple dermatofibromas are exceedingly rare. Our presentation appears to be only the second report of multiple dermatofibromas in association with an autoimmune disease and immunosuppressive medication. In the cases of Newman and Walter' and in our case, there appears to be a causeand-effect relationship, although the tumors have persisted in our patient for 2 years in spite of no further immunosuppressive medication. *Walter J: Personal communication, October, 1983.
REFERENCES 1. Newman M, Walter JB: Multiple dermatofibromas in patients with systemic lupus erythematosus on immunosuppressive therapy. N Engl J Med 289:842-843, 1973. 2. Baraf CS, Shapiro L: Multiple histiocytomas. Arch DermatoI 101:588-590, 1970. 3. Winkelmann RK, Muller SA: Generalized eruptive histiocytomas. A benign papular histiocytic reticulosis. Arch Dermatol 88:586-596, 1963.
Denrtatofibromas are common, benign intradermal nodules that appear to be more common in worrien. T~e cause is unknown, although a viral infection has been suggested. I They are known by several other names, including histiocytoma, nodular subepidermal fibrosis, and sclerosing hemarigioma. We wish to report the case of a middleaged man who developed numerous dermatofibromas following a diagnosis of myasthenia gravis and treatment with immuosuppressive medications. CASE REPORT The patient is a 53-year-old businessman who was well until January, 1979, when he presented to his family physician with a week's history of increasing muscle weakness brought on by exercise. The weakness especially involved the neck, eyelids, and shoulder girdle muscles. By the end of a game of racquetball, the patient would literally have to support his head with his hands. Referral was made to a neurologist, who confirmed the suspicion of myasthenia gravis by administering a From the Sunnybrook Medical Center, and Scarborough General Hospital. Reprint requests to: Dr. Howard Bargman, 2927 Lawrence Ave. E, Scarborough, Ontario M1P 2T5, Canada.
tensilon test with strongly positive results. At that time, the results of thyroid tests, blood urea rlitrogen tests, aspartate aminotransferase determination, antinuclear antibody tests, protein electrophoresis, and hemoglobin tests were all within normal limits. An x-ray of the chest did not suggest the presence of thymoma. Electromyogram showed typical responses suggestive of myasthenia gravis. The patient was started on a regimen of neostigmine six times a day, and his symptoms improved. No abnormalities of the skin were ever noted during this period. The patient was seen next in April, 1980, by another physician, who started him on prednisone, 100 mg/day, for systemic effect. A poor response prompted further search for thymoma, which was subsequently discovered and then surgically removed. The prednisone dose was reduced to 100 mg every either day, and cyclophosphamide, 50 mg/day, was begun and subsequently continued for 18 months. Pyridostigmine bromide (Mestinon) and epinephrine were given for short periods. Approximately 4 months after starting the cyclophosphamide, the patient noted the onset of skin growths that were firm, hyperpigmented, and asymptomatic. They continued to app~ar and to increase in size for many months. Dermatologic consultation was sought, and apparently the lumps were dismissed. It is not known whether a diagnosis was established at that time.
351
Journal of the American Academy of Dermatology
352 Bargman and Fefferman
Fig. 1. Medial aspect of the right thigh and leg, showing
multiple pigmented dennatofibromas. The lesions are larger than those which tend to be found in the nonnal individual.
All medications have now been discontinued for the last 2 years, and the patient feels completely well. There has been no change in the lesions since the medication was stopped. He is active in both business and sports, and in fact it was not until he played tennis with one of the authors (H. B. B.) that any interest in his skin was generated. Examination of the skin revealed approximately fifty to seventy finn, hyperpigmented intracutaneous nodules scattered over the legs (Fig. 1), anns, and trunk. These lesions measured as large as 1.3 em in diameter. Biopsy of a lesion from the left leg revealed the typical histologic picture of dennatofibroma.
DISCUSSION
Myasthenia gravis is a relatively uncommon disease of the neuromuscular junction. An autoimmune process is suspected because it is frequently associated with thyroid abnormalities and/or thymoma. It frequently improves after the thymoma is treated either by surgery or by x-ray therapy. Immunosuppressive drugs are sometimes beneficial, and in this case prednisone and cyclophosphamide were given. Dermatofibromas are common benign tumors of the skin and are probably seen daily in any busy dermatologic practice. They are few in number, tend to be less than 5 mm in diameter, and usually occur only on the legs, although they can be seen on the trunk and the arms. What is interesting in this case is the fact that the dermatofibromas began shortly after cyclosphosphamide was added to the
treatment schedule. Such a finding is not without precedent. Newman and Walter l reported four cases of multiple dennatofibromas in four women with systemic lupus erythematosus who had been receiving immunosuppressive therapy consisting of prednisone, azathioprine, or both. The lesions were not as numerous as in our case, and their size appeared to fall within nonnal range. The histologic picture of these dermatofibromas did not differ from that of the typical solitary kind. * Multiple dermatofibromas (greater than fifteen in number) in a normal patient are rare. Baraf and Shapir02 report a case of a 39-year-old woman with sixty-one lesions varying in size from 3 to 10 mm and were able to document only four previously reported cases. Their patient was healthy, but of the other four patients, one had diabetes and hydronephrosis and another had hypercholesterolemia and glycosuria. Winklemann and Muller reported on generalized eruptive histiocytoma and referred to four other reports. In this condition, healthy adults develop generalized symmetric, discrete, flesh-colored to bluish-red papules with no tendency toward grouping. The process "seems more closely related to the first histiocytic stage of nevoxanthoendothelioma than to the classic solitary dermatofibromas. "3 Multiple dermatofibromas are exceedingly rare. Our presentation appears to be only the second report of multiple dermatofibromas in association with an autoimmune disease and immunosuppressive medication. In the cases of Newman and Walter' and in our case, there appears to be a causeand-effect relationship, although the tumors have persisted in our patient for 2 years in spite of no further immunosuppressive medication. *Walter J: Personal communication, October, 1983.
REFERENCES 1. Newman M, Walter JB: Multiple dermatofibromas in patients with systemic lupus erythematosus on immunosuppressive therapy. N Engl J Med 289:842-843, 1973. 2. Baraf CS, Shapiro L: Multiple histiocytomas. Arch DermatoI 101:588-590, 1970. 3. Winkelmann RK, Muller SA: Generalized eruptive histiocytomas. A benign papular histiocytic reticulosis. Arch Dermatol 88:586-596, 1963.