- Email: [email protected]
Topical methotrexate for lymphomatoid papulosis
Case reports 937
J AM ACAD DERMATOL VOLUME 49, NUMBER 5
Topical methotrexate for lymphomatoid papulosis Jane S. Bergstrom, MD,a and Christine Jaworsky, MDb Cleveland, Ohio Lymphomatoid papulosis is a lymphoproliferative disease characterized by recurrent papules, nodules, or plaques that spontaneously involute within several weeks. Despite having a histologically malignantappearing infiltrate, patients with lymphomatoid papulosis have a clinically benign course. Several treatment options have been described for the management of lymphomatoid papulosis. We describe a patient who had complete resolution of lesions with the use of topical methotrexate. (J Am Acad Dermatol 2003; 49:937-9.)
A
s first described by Macaulay,1 lymphomatoid papulosis is a continuing, self-healing eruption that is clinically benign but histologically malignant in appearance. Papules, nodules, or plaques occur in crops, grow rapidly over a few days, ulcerate, and then heal over several weeks with scarring. The cycle of eruptions might recur randomly for decades. The disease frequently occurs in the middle aged and affects both sexes equally. Two histologic subtypes have been described. Type A is characterized by a dermal infiltrate of Reed– Sternberg type CD30⫹ large atypical cells. Type B has mycosis fungoides–type cells with cerebriform nuclei. Approximately 10% of cases are associated with synchronous or asynchronous mycosis fungoides, CD30⫹ large cell lymphoma, or Hodgkin’s disease.2 Several treatment options for lymphomatoid papulosis have been described, including observation, oral antibiotics, surgical excision, oral or subcutaneous methotrexate, psoralen ultraviolet A, topical carmustine, intralesional corticosteroids, and intralesional IFN-␣2b, or radiation therapy.2,3 We report a case in which resolution of lymphomatoid From the Departments of Dermatology at the University Hospitals of Cleveland,a and Case Western Reserve University, MetroHealth Medical Center.b Funding sources: None. Conflict of interest: None identified. Accepted for publication December 2, 2001. Reprint requests: Christine Jaworsky, MD, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/S0190-9622(03)00470-5
papulosis lesions was achieved through the application of methotrexate.
CASE REPORT The patient is a 71-year-old white man who was initially seen at MetroHealth Medical Center Dermatology Clinic for intermittent painful 1- to 2-cm papulonodules on his thighs, hips, arms, hands, and feet (Fig 1, A). One to 3 lesions appeared at any one time. All lesions developed a central black eschar within 1 week of onset and persisted for up to 2 months before resolution. Initially, he was treated with short courses of antibiotics, such as cephalexin and tetracycline, and excision. Histologic evaluation of 3 excised papules showed ulceration with perivascular and interstitial large atypical CD30⫹ lymphocytes with lymphocytic vasculitis (Fig 2). These pathologic findings in addition to his typical clinical presentation led to the diagnosis of lymphomatoid papulosis. His medical history consisted of insulin-requiring diabetes mellitus. He was taking no other medications, except echinacea. Total skin examination revealed no evidence of concurrent mycosis fungoides or other cutaneous lymphoma. He had no palpable lymphadenopathy. Radiographic evaluation included a chest x-ray and computed tomography scans of the abdomen and pelvis that were normal. Further evaluation included a normal blood count and differential, chemistries, erythrocyte sedimentation rate, liver enzymes, antinuclear antibodies, hepatitis panel, and serum and urine protein electrophoresis. These studies excluded extracutaneous involvement or concurrent lymphoma. The patient was started on 12.5 mg of oral methotrexate per week, which rapidly cleared his lesions.
938 Case reports
Fig 1. A, Lymphomatoid papulosis on the right inner thigh left untreated 3 days after onset. B, Lymphomatoid papulosis on the left groin 1 day after treatment with topically applied methotrexate. C, Lymphomatoid papulosis, same lesion as in B on day 9 of topical methotrexate therapy. Although this lesion has persisted slightly longer than usual, with treatment, it is still notably smaller than previous lesions not treated.
He had no new lesions develop on this regimen. After 3 months, the patient decided to discontinue methotrexate, because he thought the risks of systemic therapies outweighed their possible benefits. He quickly had a recurrence with crops of 2 to 4 lesions. He then started his own formulation of topical methotrexate. He moistened a 2.5-mg tablet of methotrexate with tap water and rubbed it onto a bandage until the gauze turned orange. He then applied this bandage daily on newly formed papules. He used approximately one third of a tablet (0.83 mg) per lesion per day. With this regimen, his lesions regressed within 2 to 3 days, and rarely took up to a week to resolve (Fig 1, B and C). The papules were smaller (5-10 mm) and rarely ulcerated. Lesions not treated in this manner grew larger, up to 2 cm, and persisted for more than 3 weeks. After 1 year of follow-up, he continued to have crops of 1 to 3 papules develop approximately every other month. However, he was able to control the extent of these lesions and prevent scar formation with the topical application of methotrexate to new lesions. No lymphoma has been identified in this patient to date, and his laboratory studies remain unchanged.
DISCUSSION Standard treatments for lymphomatoid papulosis include observation, oral antibiotics, surgical excision, methotrexate, psoralens ultraviolet A, topical carmustine, intralesional corticosteroids, or IFN-␣2b, or radiation.3 We are the first to report the use of topical methotrexate for lymphomatoid papulosis as an alternative treatment modality. Although the individual lesions usually undergo spontaneous resolution, the patient has documented a shorter dura-
J AM ACAD DERMATOL NOVEMBER 2003
Fig 2. A, Histologic section shows an ulcerated nodule with dermal hemorrhage. (Hematoxylin-eosin stain; original magnification ⫻20.) B, On high-power view, the dermal infiltrate consists of highly atypical mononuclear cells that were CD30 positive. (Hematoxylin-eosin stain; original magnification ⫻400.)
tion of lesions with topical therapy than with no therapy. We therefore believe that the topical application of methotrexate promotes faster recovery and with less ulceration. It is unclear what the bioavailability of methotrexate is in a “tap water” vehicle; however, the drug is believed to have poor transcutaneous absorption.4 In 1 study by Lu et al,5 in which the pharmacokinetics of methotrexate were studied using an absorption enhancer, the bioavailability was 11.8% ⫾ 3%. Hence, in our patient, because he used no enhancers for methotrexate absorption, we believe he had minimal systemic absorption of the active drug. Thus, systemic side effects of methotrexate such as bone marrow suppression, liver, and pulmonary toxicity might be avoided by use of the topical route. Furthermore, in this patient, his total dose was extremely small, approximately 7.5 mg topically every other month. Topical methotrexate, however, is not currently available for dermatologic use. There have been previous attempts to use it topically for psoriasis, but studies failed to show significant efficacy, possibly because of inadequate percutaneous absorption.6 Despite multiple attempts by the pharmaceutical industry to increase its bioavailability with various absorption enhancers, topical methotrexate still yielded poor results in psoriasis. However, mouse studies suggest that topical methotrexate has local activity resulting in inhibition of DNA synthesis and epidermal atrophy.4 Lymphomatoid papulosis is thought to be exquisitely responsive to lower doses of oral or subcutaneous methotrexate compared with psoriasis.7 This disease therefore might require less percutaneous absorption for a clinical response than might be
Case reports 939
J AM ACAD DERMATOL VOLUME 49, NUMBER 5
necessary for psoriasis and hence might explain our patient’s excellent clinical response. There are no data to suggest that oral or subcutaneous methotrexate prevents progression to lymphoma in patients with lymphomatoid papulosis.7 Hence, it is even less clear whether a topical formulation of this drug would provide this benefit. Nonetheless, topical methotrexate might be an attractive alternative with few side effects for the symptomatic treatment of limited lymphomatoid papulosis. REFERENCES 1. Macaulay WL. Lymphomatoid papulosis update. Arch Dermatol 1989;125:1387-9. 2. Wood GS. Inflammatory diseases that simulate lymphomas: cutaneous pseudolymphomas. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz ST, et al, editors. Fitzpatrick’s der-
3. 4.
5.
6.
7.
matology in general medicine. 5th ed. New York: McGraw-Hill; 1999. p. 1259-74. Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermatol 1994;30:379-95. Ball MA, McCullough JL, Weinstein GD. Percutaneous absorption of methotrexate: effect on epidermal DNA synthesis in hairless mice. J Invest Dermatol 1982;79:7-10. Lu GW, Jun HW, Dzimianski MT, Qui HC, McCall JW. Pharmacokinetic studies of methotrexate in plasma and synovial fluid following i.v. bolus and topical routes of administration in dogs. Pharm Res 1995;12:1474-7. Bjerring P, Beck HI, Zachariae H, Sogaard H. Topical treatment of psoriatic skin with methotrexate cream: a clinical, pharmacokinetic, and histological study. Acta Derm Venereol 1986;66: 515-9. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol 1996;34:470-81.
Beryllium dermatitis Joshua M. Berlin, MD,a James S. Taylor, MD,a Jessica E. Sigel, MD,b Wilma F. Bergfeld, MD,a and Raed A. Dweik, MDc Cleveland, Ohio Chronic beryllium disease is a granulomatous disorder characterized by a cell-mediated immune response to beryllium. Most reports of chronic beryllium disease discuss pulmonary and noncutaneous immunologic findings. This report of occupational chronic beryllium disease emphasizes cutaneous findings and discusses the potential role of skin exposure in the disease. (J Am Acad Dermatol 2003;49:939-41.)
C
utaneous manifestations to beryllium exposure were first described in 1951.1 Since this initial compilation of patients by Curtis, 5 classes of beryllium skin disease have been described: irritant contact dermatitis, allergic contact dermatitis, chemical ulcers, ulcerating granulomas, and allergic dermal granulomas. We report a case in which cutaneous beryllium disease was present before subjective pulmonary complaints.
CASE REPORT A 29-year-old white man was referred for evaluation of a 4-month history of a papular eruption on his arms, left thigh, and right knee. The patient’s From the Departments of Dermatology,a Pathology,b and Pulmonary & Critical Care Medicine,c Cleveland Clinic Foundation. Funding sources: None. Conflict of interest: None identified. Reprint requests: Raed A. Dweik, MD, Department of Pulmonary and Critical Care Medicine, A-90, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/S0190-9622(03)01555-X
medical history was remarkable for infectious mononucleosis 1 month earlier, and his only medication was a multivitamin supplement. He had been employed at a factory for the past 3.5 years, where he operated a beryllium-alloy production furnace that melted beryllium, copper, cobalt, zirconium, and nickel. Treatment with a 2-week course of systemic corticosteroids and mid-potency topical steroids had been unsuccessful. Because he had chronic exposure to beryllium, the factory monitored pulmonary function tests on a routine basis. He had been referred to pulmonary medicine for further evaluation after a decline in his diffusion lung capacity from 133% predicted in March of 1998 to 97% predicted in March of 1999. A routine chest x-ray film and highresolution computed tomography scan of the chest revealed no evidence of disease, bronchoscopy with bronchoalveolar lavage and transbronchial biopsies revealed no evidence of granulomas or other signs of disease, and both bronchoalveolar lavage lymphocyte proliferation test and blood lymphocytic proliferation test for beryllium were negative. In the fall of 1999, the patient’s diffusion lung capacity was rechecked and had increased to 109% of predicted.
J AM ACAD DERMATOL VOLUME 49, NUMBER 5
Topical methotrexate for lymphomatoid papulosis Jane S. Bergstrom, MD,a and Christine Jaworsky, MDb Cleveland, Ohio Lymphomatoid papulosis is a lymphoproliferative disease characterized by recurrent papules, nodules, or plaques that spontaneously involute within several weeks. Despite having a histologically malignantappearing infiltrate, patients with lymphomatoid papulosis have a clinically benign course. Several treatment options have been described for the management of lymphomatoid papulosis. We describe a patient who had complete resolution of lesions with the use of topical methotrexate. (J Am Acad Dermatol 2003; 49:937-9.)
A
s first described by Macaulay,1 lymphomatoid papulosis is a continuing, self-healing eruption that is clinically benign but histologically malignant in appearance. Papules, nodules, or plaques occur in crops, grow rapidly over a few days, ulcerate, and then heal over several weeks with scarring. The cycle of eruptions might recur randomly for decades. The disease frequently occurs in the middle aged and affects both sexes equally. Two histologic subtypes have been described. Type A is characterized by a dermal infiltrate of Reed– Sternberg type CD30⫹ large atypical cells. Type B has mycosis fungoides–type cells with cerebriform nuclei. Approximately 10% of cases are associated with synchronous or asynchronous mycosis fungoides, CD30⫹ large cell lymphoma, or Hodgkin’s disease.2 Several treatment options for lymphomatoid papulosis have been described, including observation, oral antibiotics, surgical excision, oral or subcutaneous methotrexate, psoralen ultraviolet A, topical carmustine, intralesional corticosteroids, and intralesional IFN-␣2b, or radiation therapy.2,3 We report a case in which resolution of lymphomatoid From the Departments of Dermatology at the University Hospitals of Cleveland,a and Case Western Reserve University, MetroHealth Medical Center.b Funding sources: None. Conflict of interest: None identified. Accepted for publication December 2, 2001. Reprint requests: Christine Jaworsky, MD, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/S0190-9622(03)00470-5
papulosis lesions was achieved through the application of methotrexate.
CASE REPORT The patient is a 71-year-old white man who was initially seen at MetroHealth Medical Center Dermatology Clinic for intermittent painful 1- to 2-cm papulonodules on his thighs, hips, arms, hands, and feet (Fig 1, A). One to 3 lesions appeared at any one time. All lesions developed a central black eschar within 1 week of onset and persisted for up to 2 months before resolution. Initially, he was treated with short courses of antibiotics, such as cephalexin and tetracycline, and excision. Histologic evaluation of 3 excised papules showed ulceration with perivascular and interstitial large atypical CD30⫹ lymphocytes with lymphocytic vasculitis (Fig 2). These pathologic findings in addition to his typical clinical presentation led to the diagnosis of lymphomatoid papulosis. His medical history consisted of insulin-requiring diabetes mellitus. He was taking no other medications, except echinacea. Total skin examination revealed no evidence of concurrent mycosis fungoides or other cutaneous lymphoma. He had no palpable lymphadenopathy. Radiographic evaluation included a chest x-ray and computed tomography scans of the abdomen and pelvis that were normal. Further evaluation included a normal blood count and differential, chemistries, erythrocyte sedimentation rate, liver enzymes, antinuclear antibodies, hepatitis panel, and serum and urine protein electrophoresis. These studies excluded extracutaneous involvement or concurrent lymphoma. The patient was started on 12.5 mg of oral methotrexate per week, which rapidly cleared his lesions.
938 Case reports
Fig 1. A, Lymphomatoid papulosis on the right inner thigh left untreated 3 days after onset. B, Lymphomatoid papulosis on the left groin 1 day after treatment with topically applied methotrexate. C, Lymphomatoid papulosis, same lesion as in B on day 9 of topical methotrexate therapy. Although this lesion has persisted slightly longer than usual, with treatment, it is still notably smaller than previous lesions not treated.
He had no new lesions develop on this regimen. After 3 months, the patient decided to discontinue methotrexate, because he thought the risks of systemic therapies outweighed their possible benefits. He quickly had a recurrence with crops of 2 to 4 lesions. He then started his own formulation of topical methotrexate. He moistened a 2.5-mg tablet of methotrexate with tap water and rubbed it onto a bandage until the gauze turned orange. He then applied this bandage daily on newly formed papules. He used approximately one third of a tablet (0.83 mg) per lesion per day. With this regimen, his lesions regressed within 2 to 3 days, and rarely took up to a week to resolve (Fig 1, B and C). The papules were smaller (5-10 mm) and rarely ulcerated. Lesions not treated in this manner grew larger, up to 2 cm, and persisted for more than 3 weeks. After 1 year of follow-up, he continued to have crops of 1 to 3 papules develop approximately every other month. However, he was able to control the extent of these lesions and prevent scar formation with the topical application of methotrexate to new lesions. No lymphoma has been identified in this patient to date, and his laboratory studies remain unchanged.
DISCUSSION Standard treatments for lymphomatoid papulosis include observation, oral antibiotics, surgical excision, methotrexate, psoralens ultraviolet A, topical carmustine, intralesional corticosteroids, or IFN-␣2b, or radiation.3 We are the first to report the use of topical methotrexate for lymphomatoid papulosis as an alternative treatment modality. Although the individual lesions usually undergo spontaneous resolution, the patient has documented a shorter dura-
J AM ACAD DERMATOL NOVEMBER 2003
Fig 2. A, Histologic section shows an ulcerated nodule with dermal hemorrhage. (Hematoxylin-eosin stain; original magnification ⫻20.) B, On high-power view, the dermal infiltrate consists of highly atypical mononuclear cells that were CD30 positive. (Hematoxylin-eosin stain; original magnification ⫻400.)
tion of lesions with topical therapy than with no therapy. We therefore believe that the topical application of methotrexate promotes faster recovery and with less ulceration. It is unclear what the bioavailability of methotrexate is in a “tap water” vehicle; however, the drug is believed to have poor transcutaneous absorption.4 In 1 study by Lu et al,5 in which the pharmacokinetics of methotrexate were studied using an absorption enhancer, the bioavailability was 11.8% ⫾ 3%. Hence, in our patient, because he used no enhancers for methotrexate absorption, we believe he had minimal systemic absorption of the active drug. Thus, systemic side effects of methotrexate such as bone marrow suppression, liver, and pulmonary toxicity might be avoided by use of the topical route. Furthermore, in this patient, his total dose was extremely small, approximately 7.5 mg topically every other month. Topical methotrexate, however, is not currently available for dermatologic use. There have been previous attempts to use it topically for psoriasis, but studies failed to show significant efficacy, possibly because of inadequate percutaneous absorption.6 Despite multiple attempts by the pharmaceutical industry to increase its bioavailability with various absorption enhancers, topical methotrexate still yielded poor results in psoriasis. However, mouse studies suggest that topical methotrexate has local activity resulting in inhibition of DNA synthesis and epidermal atrophy.4 Lymphomatoid papulosis is thought to be exquisitely responsive to lower doses of oral or subcutaneous methotrexate compared with psoriasis.7 This disease therefore might require less percutaneous absorption for a clinical response than might be
Case reports 939
J AM ACAD DERMATOL VOLUME 49, NUMBER 5
necessary for psoriasis and hence might explain our patient’s excellent clinical response. There are no data to suggest that oral or subcutaneous methotrexate prevents progression to lymphoma in patients with lymphomatoid papulosis.7 Hence, it is even less clear whether a topical formulation of this drug would provide this benefit. Nonetheless, topical methotrexate might be an attractive alternative with few side effects for the symptomatic treatment of limited lymphomatoid papulosis. REFERENCES 1. Macaulay WL. Lymphomatoid papulosis update. Arch Dermatol 1989;125:1387-9. 2. Wood GS. Inflammatory diseases that simulate lymphomas: cutaneous pseudolymphomas. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz ST, et al, editors. Fitzpatrick’s der-
3. 4.
5.
6.
7.
matology in general medicine. 5th ed. New York: McGraw-Hill; 1999. p. 1259-74. Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermatol 1994;30:379-95. Ball MA, McCullough JL, Weinstein GD. Percutaneous absorption of methotrexate: effect on epidermal DNA synthesis in hairless mice. J Invest Dermatol 1982;79:7-10. Lu GW, Jun HW, Dzimianski MT, Qui HC, McCall JW. Pharmacokinetic studies of methotrexate in plasma and synovial fluid following i.v. bolus and topical routes of administration in dogs. Pharm Res 1995;12:1474-7. Bjerring P, Beck HI, Zachariae H, Sogaard H. Topical treatment of psoriatic skin with methotrexate cream: a clinical, pharmacokinetic, and histological study. Acta Derm Venereol 1986;66: 515-9. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol 1996;34:470-81.
Beryllium dermatitis Joshua M. Berlin, MD,a James S. Taylor, MD,a Jessica E. Sigel, MD,b Wilma F. Bergfeld, MD,a and Raed A. Dweik, MDc Cleveland, Ohio Chronic beryllium disease is a granulomatous disorder characterized by a cell-mediated immune response to beryllium. Most reports of chronic beryllium disease discuss pulmonary and noncutaneous immunologic findings. This report of occupational chronic beryllium disease emphasizes cutaneous findings and discusses the potential role of skin exposure in the disease. (J Am Acad Dermatol 2003;49:939-41.)
C
utaneous manifestations to beryllium exposure were first described in 1951.1 Since this initial compilation of patients by Curtis, 5 classes of beryllium skin disease have been described: irritant contact dermatitis, allergic contact dermatitis, chemical ulcers, ulcerating granulomas, and allergic dermal granulomas. We report a case in which cutaneous beryllium disease was present before subjective pulmonary complaints.
CASE REPORT A 29-year-old white man was referred for evaluation of a 4-month history of a papular eruption on his arms, left thigh, and right knee. The patient’s From the Departments of Dermatology,a Pathology,b and Pulmonary & Critical Care Medicine,c Cleveland Clinic Foundation. Funding sources: None. Conflict of interest: None identified. Reprint requests: Raed A. Dweik, MD, Department of Pulmonary and Critical Care Medicine, A-90, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/S0190-9622(03)01555-X
medical history was remarkable for infectious mononucleosis 1 month earlier, and his only medication was a multivitamin supplement. He had been employed at a factory for the past 3.5 years, where he operated a beryllium-alloy production furnace that melted beryllium, copper, cobalt, zirconium, and nickel. Treatment with a 2-week course of systemic corticosteroids and mid-potency topical steroids had been unsuccessful. Because he had chronic exposure to beryllium, the factory monitored pulmonary function tests on a routine basis. He had been referred to pulmonary medicine for further evaluation after a decline in his diffusion lung capacity from 133% predicted in March of 1998 to 97% predicted in March of 1999. A routine chest x-ray film and highresolution computed tomography scan of the chest revealed no evidence of disease, bronchoscopy with bronchoalveolar lavage and transbronchial biopsies revealed no evidence of granulomas or other signs of disease, and both bronchoalveolar lavage lymphocyte proliferation test and blood lymphocytic proliferation test for beryllium were negative. In the fall of 1999, the patient’s diffusion lung capacity was rechecked and had increased to 109% of predicted.