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Morbilliform Skin Eruption Owing to Diethylstilbestrol
0022-534 7/84/1314-0767$02.00 /0 Vol. 131, April
THE JOURNAL OF UROLOGY
Copyright© 1984 by The Williams & Wilkins Co.
Printed in U.S.A.
MORBILLIFORM SKIN ERUPTION OWING TO DIETHYLSTILBESTROL MARY LEE AND ROOHOLLAH SHARIFI From the College of Pharmacy and College of Medicine, Section of Urology, University of Illinois, Chicago, Illinois
ABSTRACT
We describe an unusual case of morbilliform skin eruption caused by diethylstilbestrol in a patient with stage D prostatic cancer. A widespread erythematous maculopapular rash and urticaria appeared with repeated challenges of diethylstilbestrol and resolved with drug withdrawal. In addition, the literature on various types of dermatitis medicamentosa in male patients with prostatic cancer treated with diethylstilbestrol is reviewed. We describe a rare case of a morbilliform skin eruption owing to diethylstilbestrol in a patient with prostatic cancer. Despite frequent use of diethylstilbestrol in urological patients this adverse reaction has not been reported previously in male patients. CASE REPORT
D. M., a 74-year-old Hispanic man, was in good health until January 1981 when he was hospitalized for acute urinary retention. Rectal examination revealed an enlarged, firm prostate. Serum acid phosphatase was twice normal. An excretory urogram showed a normal upper urinary tract with bladder neck obstruction. Cystoscopy revealed marked trabeculations of the bladder and trilobar prostatic hypertrophy with outlet obstruction. Prostatic needle biopsy showed moderately well differentiated adenocarcinoma. Bone survey, and bone and liver scans were normal. Based on a presumptive diagnosis of stage D prostatic carcinoma, the patient underwent transurethral resection of the prostate and was started promptly on 1 mg. diethylstilbestrol daily. The patient was rehospitalized 3 weeks later with the onset of hemoptysis and pleuritic chest pain, and a pulmonary embolus was found. Diethylstilbestrol was stopped and anticoagulants were initiated. During the next 3 months the prostatic cancer progressed, as evidenced by an increase in serum acid phosphatase to 4 times normal and appearance of metastases on the bone scan. Therefore, bilateral orchiectomy was done. Subsequently, the serum acid phosphatase returned to normal, and the patient appeared to respond and did well for the next year. However, 16 months after orchiectomy the patient complained of severe back pain, which was treated with 1,600 mg. ibuprofen daily. Meanwhile, serum acid phosphatase increased to 2.5 times normal and a repeat bone scan revealed new metastatic lesions. With this evidence of tumor progression, 1 mg. enteric-coated diethylstilbestrol daily was begun. After 4 doses the patient complained of a nonpruritic skin rash. On examination, there were numerous, erythematous maculae and papules distributed over the entire body but most prevalent on the chest, abdomen and back. Some of the lesions were in an annular configuration. No mucosal or target lesions were seen. The patient denied drug or food allergies. Ibuprofen and diethylstilbestrol were stopped and, while the patient was taking no medication, the maculopapular rash disappeared within 1 week. Plain white tablets of 1 mg. diethylstilbestrol daily were started. Urticaria and erythematous papules reappeared over the entire body after 2 doses, except this time the eruptions predominately covered the lower legs bilaterally, with coverage being greater on the left side (see figure). In addition, the patient complained of itching. A complete hematologic diagnostic study was unreAccepted for publication October 21, 1983.
vealing. Diethylstilbestrol was stopped and the morbilliform skin eruption disappeared during the next few days. DISCUSSION
Despite its frequent use in male urological patients diethylstilbestrol rarely produces dermatologic adverse reactions. 1 Al-
Upon rechallenge with diethylstilbestrol patient suffered erythematous morbilliform skin eruption. Maculopapular lesions appeared on abdomen, chest and back but were more severe on lower extremities.
though chloasma, erythema multiforme, erythema nodosum, hirsutism, alopecia, purpura, maculopapular rash, brawny erythema2 and photosensitivity reactions have been reported, these have occurred predominantly in female patients taking estrogen-containing oral contraceptives or in menopausal women on estrogen replacement regimens. Only a few reports of dermatitis medicamentosa in male patients could be found in the literature, including periarterit is nodosa in a 34-year-old black man (female impersonator) taking 100 mg. diethylstilbestrol daily for >6 months3 and acanthosis nigricans in 2 boys with childhood muscular dystrophy who were treated with 5 mg. diethylstilbestrol daily for > 18 months.4 If only male patients with prost atic cancer are considered, those dermatologic adverse reactions attributed to diethylstilbestrol have been limited to the skin lesions of porphyria cutanea tarda in genetically susceptible patients,n-9 papillomatosis and hyperkeratosis of the breast nipple, 10• 11 and hemorrhagic purpura, 12 • 1'1 We describe an unusual case of diethylstilbestrol-induced morbilliform skin eruption. Because we were uncertain as to the cause of the rash when it first appeared ibuprofen and enteric-coated diethylstilbestrol tablets were stopped. Hor-
768
LEE AND SHARIFI
monal treatment with uncoated diethylstilbestrol tablets was attempted to avoid possible hypersensitivity reactions to dyes or additives in tablet coatings. Despite this maneuver, rechallenge with diethylstilbestrol resulted in reappearance of the rash. Although the pathogenesis of diethylstilbestrol-induced morbilliform skin eruption is not known, we suspect an immunologic mechanism. Previous diethylstilbestrol exposure, history of intermittent drug use, quick onset of the skin eruption with rechallenge and improvement with drug withdrawal, and the systemic distribution of skin lesions are highly suggestive of a hypersensitivity reaction in this patient. In conclusion, dermatologic adverse reactions caused by diethylstilbestrol in male patients are rare. We describe the first case of morbilliform skin eruption, which complicated and limited treatment with diethylstilbestrol in a patient with prostatic cancer. Since urologists frequently prescribe estrogens, they should be aware of this possible side effect of diethylstilbestrol. REFERENCES l. Bruinsma, W.: A Guide to Drug Eruptions. Amsterdam: Excerpta
Medica, p. 83, 1973. 2. Shorr, E., Robinson, F. H. and Papanicolaou, G. N.: A clinical study of the synthetic estrogen stilbestrol. J.A.M.A., 113: 2312, 1939. 3. Keyloun, V., Halperin, I. and Grace, W. J.: Periarteritis nodosa caused by hypersensitivity to estrogens. Vase. Dis., 4: 21, 1967.
4. Banuchi, S. R., Cohen, L., Lorincz, A. L. and Morgan, J.: Acanthosis nigricans following diethylstilbestrol therapy. Occurrence in patients with childhood muscular dystrophy. Arch. Dermatol., 109: 545, 1974. 5. Roenigk, H. H., Jr. and Gottlob, M. E.: Estrogen-induced porphyria cutanea tarda. Report of three cases. Arch. Dermatol., 102: 260, 1970. 6. Malina, L. and Chlumsky, J.: Oestrogen-induced familial porphyria cutanea tarda. Brit. J. Dermatol., 92: 707, 1975. 7. Stein, K. M., Raque, C. J., Zeigerman, J. H. and Shrager, J. D.: Porphyria cutanea tarda induced by natural estrogens. A case report. Obst. Gynec., 38: 755, 1971. 8. Weimar, V. M., Weimar, G. W. and Ceilley, R. I.: Estrogen-induced porphyria cutanea tarda complicating treatment of prostatic carcinoma. J. Urol., 120: 643, 1978. 9. Vail, J. T., Jr.: Porphyria cutanea tarda and estrogens. J.A.M.A., 201: 671, 1967. 10. Waldo, E. D., Sidhu, G. S. and Hu, A. W.: Florid papillomatosis of male nipple after diethylstilbestrol therapy. Arch. Path., 99: 364, 1975. 11. Mold, D. E. and Jegasothy, B. V.: Estrogen-induced hyperkeratosis of the nipple. Cutis, 26: 95, 1980. 12. Herbst, W. P.: Thoughts and observations on the relation of altered hormonal balance to prostatic malignancy. Urol. Cutan. Rev., 45: 691, 1942. 13. Watson, C. J., Schultz, A. L. and Wikoff, H. M.: Purpura following estrogen therapy, with particular reference to hypersensitivity to (diethyl) stilbestrol and with a note on the possible relationship of purpura to endogenous estrogens. J. Lab. Clin. Med., 32: 606, 1947.
THE JOURNAL OF UROLOGY
Copyright© 1984 by The Williams & Wilkins Co.
Printed in U.S.A.
MORBILLIFORM SKIN ERUPTION OWING TO DIETHYLSTILBESTROL MARY LEE AND ROOHOLLAH SHARIFI From the College of Pharmacy and College of Medicine, Section of Urology, University of Illinois, Chicago, Illinois
ABSTRACT
We describe an unusual case of morbilliform skin eruption caused by diethylstilbestrol in a patient with stage D prostatic cancer. A widespread erythematous maculopapular rash and urticaria appeared with repeated challenges of diethylstilbestrol and resolved with drug withdrawal. In addition, the literature on various types of dermatitis medicamentosa in male patients with prostatic cancer treated with diethylstilbestrol is reviewed. We describe a rare case of a morbilliform skin eruption owing to diethylstilbestrol in a patient with prostatic cancer. Despite frequent use of diethylstilbestrol in urological patients this adverse reaction has not been reported previously in male patients. CASE REPORT
D. M., a 74-year-old Hispanic man, was in good health until January 1981 when he was hospitalized for acute urinary retention. Rectal examination revealed an enlarged, firm prostate. Serum acid phosphatase was twice normal. An excretory urogram showed a normal upper urinary tract with bladder neck obstruction. Cystoscopy revealed marked trabeculations of the bladder and trilobar prostatic hypertrophy with outlet obstruction. Prostatic needle biopsy showed moderately well differentiated adenocarcinoma. Bone survey, and bone and liver scans were normal. Based on a presumptive diagnosis of stage D prostatic carcinoma, the patient underwent transurethral resection of the prostate and was started promptly on 1 mg. diethylstilbestrol daily. The patient was rehospitalized 3 weeks later with the onset of hemoptysis and pleuritic chest pain, and a pulmonary embolus was found. Diethylstilbestrol was stopped and anticoagulants were initiated. During the next 3 months the prostatic cancer progressed, as evidenced by an increase in serum acid phosphatase to 4 times normal and appearance of metastases on the bone scan. Therefore, bilateral orchiectomy was done. Subsequently, the serum acid phosphatase returned to normal, and the patient appeared to respond and did well for the next year. However, 16 months after orchiectomy the patient complained of severe back pain, which was treated with 1,600 mg. ibuprofen daily. Meanwhile, serum acid phosphatase increased to 2.5 times normal and a repeat bone scan revealed new metastatic lesions. With this evidence of tumor progression, 1 mg. enteric-coated diethylstilbestrol daily was begun. After 4 doses the patient complained of a nonpruritic skin rash. On examination, there were numerous, erythematous maculae and papules distributed over the entire body but most prevalent on the chest, abdomen and back. Some of the lesions were in an annular configuration. No mucosal or target lesions were seen. The patient denied drug or food allergies. Ibuprofen and diethylstilbestrol were stopped and, while the patient was taking no medication, the maculopapular rash disappeared within 1 week. Plain white tablets of 1 mg. diethylstilbestrol daily were started. Urticaria and erythematous papules reappeared over the entire body after 2 doses, except this time the eruptions predominately covered the lower legs bilaterally, with coverage being greater on the left side (see figure). In addition, the patient complained of itching. A complete hematologic diagnostic study was unreAccepted for publication October 21, 1983.
vealing. Diethylstilbestrol was stopped and the morbilliform skin eruption disappeared during the next few days. DISCUSSION
Despite its frequent use in male urological patients diethylstilbestrol rarely produces dermatologic adverse reactions. 1 Al-
Upon rechallenge with diethylstilbestrol patient suffered erythematous morbilliform skin eruption. Maculopapular lesions appeared on abdomen, chest and back but were more severe on lower extremities.
though chloasma, erythema multiforme, erythema nodosum, hirsutism, alopecia, purpura, maculopapular rash, brawny erythema2 and photosensitivity reactions have been reported, these have occurred predominantly in female patients taking estrogen-containing oral contraceptives or in menopausal women on estrogen replacement regimens. Only a few reports of dermatitis medicamentosa in male patients could be found in the literature, including periarterit is nodosa in a 34-year-old black man (female impersonator) taking 100 mg. diethylstilbestrol daily for >6 months3 and acanthosis nigricans in 2 boys with childhood muscular dystrophy who were treated with 5 mg. diethylstilbestrol daily for > 18 months.4 If only male patients with prost atic cancer are considered, those dermatologic adverse reactions attributed to diethylstilbestrol have been limited to the skin lesions of porphyria cutanea tarda in genetically susceptible patients,n-9 papillomatosis and hyperkeratosis of the breast nipple, 10• 11 and hemorrhagic purpura, 12 • 1'1 We describe an unusual case of diethylstilbestrol-induced morbilliform skin eruption. Because we were uncertain as to the cause of the rash when it first appeared ibuprofen and enteric-coated diethylstilbestrol tablets were stopped. Hor-
768
LEE AND SHARIFI
monal treatment with uncoated diethylstilbestrol tablets was attempted to avoid possible hypersensitivity reactions to dyes or additives in tablet coatings. Despite this maneuver, rechallenge with diethylstilbestrol resulted in reappearance of the rash. Although the pathogenesis of diethylstilbestrol-induced morbilliform skin eruption is not known, we suspect an immunologic mechanism. Previous diethylstilbestrol exposure, history of intermittent drug use, quick onset of the skin eruption with rechallenge and improvement with drug withdrawal, and the systemic distribution of skin lesions are highly suggestive of a hypersensitivity reaction in this patient. In conclusion, dermatologic adverse reactions caused by diethylstilbestrol in male patients are rare. We describe the first case of morbilliform skin eruption, which complicated and limited treatment with diethylstilbestrol in a patient with prostatic cancer. Since urologists frequently prescribe estrogens, they should be aware of this possible side effect of diethylstilbestrol. REFERENCES l. Bruinsma, W.: A Guide to Drug Eruptions. Amsterdam: Excerpta
Medica, p. 83, 1973. 2. Shorr, E., Robinson, F. H. and Papanicolaou, G. N.: A clinical study of the synthetic estrogen stilbestrol. J.A.M.A., 113: 2312, 1939. 3. Keyloun, V., Halperin, I. and Grace, W. J.: Periarteritis nodosa caused by hypersensitivity to estrogens. Vase. Dis., 4: 21, 1967.
4. Banuchi, S. R., Cohen, L., Lorincz, A. L. and Morgan, J.: Acanthosis nigricans following diethylstilbestrol therapy. Occurrence in patients with childhood muscular dystrophy. Arch. Dermatol., 109: 545, 1974. 5. Roenigk, H. H., Jr. and Gottlob, M. E.: Estrogen-induced porphyria cutanea tarda. Report of three cases. Arch. Dermatol., 102: 260, 1970. 6. Malina, L. and Chlumsky, J.: Oestrogen-induced familial porphyria cutanea tarda. Brit. J. Dermatol., 92: 707, 1975. 7. Stein, K. M., Raque, C. J., Zeigerman, J. H. and Shrager, J. D.: Porphyria cutanea tarda induced by natural estrogens. A case report. Obst. Gynec., 38: 755, 1971. 8. Weimar, V. M., Weimar, G. W. and Ceilley, R. I.: Estrogen-induced porphyria cutanea tarda complicating treatment of prostatic carcinoma. J. Urol., 120: 643, 1978. 9. Vail, J. T., Jr.: Porphyria cutanea tarda and estrogens. J.A.M.A., 201: 671, 1967. 10. Waldo, E. D., Sidhu, G. S. and Hu, A. W.: Florid papillomatosis of male nipple after diethylstilbestrol therapy. Arch. Path., 99: 364, 1975. 11. Mold, D. E. and Jegasothy, B. V.: Estrogen-induced hyperkeratosis of the nipple. Cutis, 26: 95, 1980. 12. Herbst, W. P.: Thoughts and observations on the relation of altered hormonal balance to prostatic malignancy. Urol. Cutan. Rev., 45: 691, 1942. 13. Watson, C. J., Schultz, A. L. and Wikoff, H. M.: Purpura following estrogen therapy, with particular reference to hypersensitivity to (diethyl) stilbestrol and with a note on the possible relationship of purpura to endogenous estrogens. J. Lab. Clin. Med., 32: 606, 1947.