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lymphoma belong to the cutaneous T-cell lymphoma category?
Volume 18 Number 2, Part 1 February 1988
systemic cyclosporine.~ The risk of nephrotoxicity may proscribe the common use of the drug in psoriasis. Page et al 2 raised the possibility that topical treatment might be effecive and safe. To test this effectiveness we conducted a study of topical cyclosporine in psoriasis. Out of a larger group, three male and 3 female patients ranging in age from 43 to 58 years (mean, 52.2 years) were selected. These patients had bilateral chronic plaque psoriasis for between 1.5 and 42 years (mean, 25.62 years), with symmetric lesions (for bilateral comparison). Patients were treated with 2 ml of an oil solution containing 5 % cyclosporine on each lesion of the upper half of the body and with the oil vehicle without eyclosporine on the contralateral side. The treatments were allocated in a random double-blind fashion to the left and right sides of the upper part of the body for 60 days. In the first 30 days the medications were applied twice a day. Thereafter, during the second month, polyethylene occlusion for 48 hours with the medications was performed on the affected areas. Patients were assessed independently by two investigators. Evaluation was performed before treatment (baseline) and once a week. Lesions were rated for erythema, plaque thickness, extension, scales, and itching. The cyclosporine blood levels of each patient were monitored by both the radioimmunoassay (RIA) and the high-pressure liquid chromatography (HPLC) methods once a week in the first month and once a fortnight thereafter. In addition, routine hematology and renal blood function tests were performed. At the end of therapy as well as during the followup, there was no difference between the cyclosporinetreated lesions and those treated with olive oil. No improvement was noted at any of the treated sites of five patients; however, an exacerbation occurred in one patient. Results of routine blood tests were unchanged. All patients failed to show any signs of systemic absorption by either the RIA or the HPLC technique, which is specific for native cyclosporine. In a companion study of topical cyclosporine treatment in ten patients with alopecia areata, the RIA detected trace levels (67, 97 ng/ml) in blood samples from two patients. However, the RIA method is less specific and probably not as effective for detection of low levels of blood cyclospofine when compared to HPLC, which gave negative results in all samples. The results of this study and a prior study of Griffiths et al3 may indicate the ineffectiveness of topical cyclosporine treatment in psoriasis. The lack of effect of topical cyclosporine treatment suggests the necessity for therapeutic blood levels of
Correspondence
379
this drug to control the psoriatic lesions. Alternatively, a topical preparation achieving epidermal penetration superior to that which we described, such as the propyl alcohol solution used by Parodi and Rebora,4 might give therapeutic results without systemic effects. The undetectable levels of the drug in the blood of our patients and previously reported patients 5 indicate minimal absorption of the drug through the skin. Notably, in patients responding to low-dose systemic therapy, measurable blood levels of cyclosporine were found.~ Finally Kato et al 6 recently provided in vitro evidence for a lack of direct effect of cyclosporine on epidermal cell growth. This further supports a systemic immunologic mechanism for the drug in psoriasis.
A. Gilhar, M.D.,* G. Winterstein, M.D.,* and D. T. Golan, M.D.** Rebecca Sieff Hospital, Safed,* Haifa Medical Center (Rothchild ), and Faculty of Medicine, Technion, Haifa,** Israel
REFERENCES 1. Griffith CEM, Powles AL, Leonard JN, et al. Clearance of psoriasis with low dose cyclosporine. Br Med J 1986;293:731-2. 2. Page EH, Wexler DM, Guenther LC. Cyclosporin A. J AM ACADDERMATOL1986;14:785-91. 3. Griffiths CEM, Powles AV, Baker BS. Topical cyclosporine and psoriasis. Lancet 1987;2:806. 4. Parodi A, Rebora A. Topical cyclosporine in alopecia areata. Arch Dermatol 1987;123:165. 5. Thomson RW, Aldridge RD, Sewell HF. Topical cyclosporine in alopecia areata and nickel contact dermatitis. Lancet 1986;2:971-2. 6. Kato N, Halprin KM, Taylor J. Cyclosporine A does not inhibit epidermal cell growth at therapeutic levels. J Invest Dermatol 1987;88:52-4.
Does adult T-cell leukemia/lymphoma belong to the cutaneous T-cell lymphoma category? To the Editor: Based on the finding that many lymphomatous malignancies with prominent cutaneous involvement are of T-cell origin, Edelson and his colleagues 1'2used the designation cutaneous T-cell lymphoma to unite the various conditions with the distinguishing clinical and cellular denominators of the primary cutaneous lymphomas. Cutaneous T-cell lymphoma constitutes a spectrum of disease that includes not only mycosis fungoides and S6zary syndrome, an erythrodermic variant of mycosis fungoides, but also other lymphoreticular neoplasms distinguished by apparent primary skin infiltration with neoplastic helper T cells. Proposal of this novel entity has brought us more extensive and fundamental understanding not only
380
Journal of the American Academy of Dermatology
Correspondence
T a b l e I. C o m p a r i s o n b e t w e e n cutaneous T-cell l y m p h o m a and adult T-cell l e u k e m i a / l y m p h o m a
Characteristics of tumor cells Geographic distribution
I Course
Skin manifestations
Phenotypes
In vitro function 1
Cutaneous T-cell lymphoma No endemic area
Chronic ~
MF: Erythematous, plaque, and tumor stages SS: Erythroderma
Helper/inducer T3 +, 4 +, 10Tac antigen -6
Help
Papules, plaques, tumors, and erythroderma
Helper/inducer T3 § 4 + , 10 + Tac antigen +
Suppression
Adult T-ceU leukemia/ lymphoma Southwest Japan, West Indies, and Southeastern United States
Acute
DNA: Deoxyribonucleicacid. 1. Assessed in the effect on polyclonal production of immunoglobulinsby pokeweedmitogen-stimulatedB cells. 2. --, Normal; 1', elevated. 3. - , Absent; +, present. 4. Some patients with cutaneous T-cell lymphoma in endemic areas in Japan are reported to be positive for antibody against HTLV-Iwithout apparent monoclonal integrations of the proviral deoxyribonucleic acid. 5. Cutaneous T-cell lymphomaoften evolves to a very aggressiveform. 6. Tac antigen indicates the interleukin-2 (IL-2) receptor. Some aggressive forms of HTLV-I-negativecutaneous T-cell lymphoma are Tacpositive. 7. Many cutaneous T-cell lymphomapatients have elevated lactic dehydrogenaselevels arising from the malignantT cells. 8. As many as 50% of adult T-cell leukemia/lymphomapatients are normocalcemJc.
of pathogenesis of cutaneous lymphoma but also of possible influence of the skin on maturation and differentiation of T ceils. Because of the broad spectrum of disease, however, the definition of cutaneous T-cell lymphoma seems to vary with the investigator. As a result, different types of cutaneous lymphomas with the helper T-ceU phenotype are included in cutaneous T-cell lymphoma, depending on how cutaneous T-cell lymphoma is defined. Adult T-cell leukemia/lymphoma is a lymphoreticular malignancy characterized by the presence of pleomorphic neoplastic cells of the mature T-cell phenotype? The disease is associated with a human retrovims designated human T-cell leukemia/lymphoma virus I (HTLV-I): Patients with adult T-ceU leukemia/lymphoma frequently develop variable skin lesions, ineluding small papules, plaques, and erythroderrna. Histologic evaluations reveal epidermotropism and Pautrier's microabscesses of tumor cells in two thirds of patients with cutaneous involvement. These findings have raised a controversial issue on the distinction of adult T-cell leukemia/lymphoma from cutaneous T-cell lymphoma: Among several points as depicted in Table I, the detection of HTLV-I infection seems to be the most important point of distinction between cutaneous T-cell
lymphoma and adult T-cell leukemia/lymphoma. This is because the presence of viral genome in malignant cells of adult T-cell leukemia/lymphoma indicates not only an aggressive course, providing an important guide for treatment and prognosis, but also infective nature of the disease as in acquired immunodeficiency syndrome. We consider that adult T-cell leukemia/lymphoma should not be included in the cutaneous T-cell lymphoma category. The proper definition of cutaneous T-ceU lymphoma and adult T-cell leukemia/lymphoma will warrant such distinction.
Masahiro Takigawa, M.D., Fumio Inoue, M.D., KeOi lwatsuki, M.D., and Mizuho Yamada, M.D. Hamamatsu University School of Medicine Hamamatsu 431-31 Japan REFERENCES 1. Edelson RL, Kirkpatrick CH, Shevach EM, et al. Preferential cutaneous infiltration by neoplastic thymusderived lymphocytes. Morphologie and functional studies. Ann Intern Med 1974;80:685-92. 2. Edelson RL. Cutaneous T cell lymphoma: mycosis fungoides, S6zary syndrome, and other variants. J AM ACAD D~RM~,'rOL 1980;2:89-106. 3. Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T cell leukemia: clinical and hematologic features of 16 cases. Blood 1977;50:481-92.
Volume 18 Number 2, Part 1 February 1988
Correspondence
381
Serum levels of 2 Monoclonal Alkaline phos- Lactic dehy- AntibodYagainstintegrationHTLV. ofl
Ca++l Ph",!ae I drogenase .TLV+'+ pro ralD. *' 7
t 8
1'
1'
+
+
4. Hinuma Y, Nagata K, Hanaoka M, et al. Antigen in an adult T-cell leukemia cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci USA 1981 ;78:6476-80. 5. Shimoyama M, Minato K, Saito H, et al. Comparison of clinical, morphologic and immunologic characteristics of adult T-cell leukemia/lymphoma and cutaneous T-cell lymphoma. Jpn J Clin Oncol 1979;9(suppl):357-72.
Fig. 1. Exudative erythematous patches and target lesions on the thighs and legs.
Erythema multiforme due to clofibrate
To the Editor: Erythema multiforme is a relatively common acute dermatosis characterized by distinct target lesions. Although a variety of etiologic factors have been implicated as precipitating erythema multiforme, there is no known provocative factor in about one half of the cases. Here we report a case of erythema multiforme due to clofibrate (ethyl c~-[parachlorophenoxy]isobutyrate, Deliva), which was confirmed by readministration test.
Case report. A 72-year-old woman was admitted to our clinic because of generalized pruritic erythematous eruption, general malaise, and fever of sudden onset. She had had mild hypertension and hyperlipidemia and had been given some hypotensive agents and clofibrate (750 mglday) for about 1 year. On the day when the eruption developed she stopped taking clofibrate on her own. On physical examination she looked ill and had a temperature of 38.5 ~ C. Extldative fresh red erythematous patches of various sizes were seen on the entire body and extremities. The extensor surfaces of the upper limbs exhibited several bullae, exudative erythematous macules, and so-called target lesions in which the center cleared, becoming cyanotic or purpuric (Fig. 1). The face and the distal parts of her limbs showed marked edema. Biopsy specimens obtained from a macular lesion on the fight thigh showed marked edema of the papillary dermis and lymphohistiocytic, patchy infiltration around the dilated small
vessels, with a moderate number of eosinophils in the upper to mid dermis (Fig. 2). Biopsy examination o f a bullous lesion disclosed subepidermal blister formation. Laboratory values were not remarkable except for strongly positive C-reactive protein ( 6 + ) . Lipid values were as follows: cholesterol, 232 mg/dl; [3-lipoprotein, 607 mg/dt; and triglyceride, 154 mg/dl. Four days after admission she became afebfile, and the rash and edema gradually disappeared over 17 days. After complete disappearance of the eruptions a test dose of 500 mg clofibrate was given with her consent. Thirty minutes after oral readministration of clofibrate she noted pruritic, erythematous maeules developing on her abdomen, buttocks, and limbs. A patch test with clofibrate showed negative findings. Photopatch test and photodrug test with clofibrate and 1% parachlorophenol (a precursor of clofibrate) also showed negative findings.
Comment. Clofibrate is used worldwide as a hypolipidemic agent. There have been only few reports of eruptions that occurred as an adverse side effect o f therapy with clofibrate. Cumming ~ reported a patient with acute renal failure and generalized erythematous rash due to clofibrate. Immunofluorescence studies suggested that the possible general hypersensitivity to clofibrate caused the renal failure and generalized rash. Clofibrate is produced from parachlorophenol by ad-
systemic cyclosporine.~ The risk of nephrotoxicity may proscribe the common use of the drug in psoriasis. Page et al 2 raised the possibility that topical treatment might be effecive and safe. To test this effectiveness we conducted a study of topical cyclosporine in psoriasis. Out of a larger group, three male and 3 female patients ranging in age from 43 to 58 years (mean, 52.2 years) were selected. These patients had bilateral chronic plaque psoriasis for between 1.5 and 42 years (mean, 25.62 years), with symmetric lesions (for bilateral comparison). Patients were treated with 2 ml of an oil solution containing 5 % cyclosporine on each lesion of the upper half of the body and with the oil vehicle without eyclosporine on the contralateral side. The treatments were allocated in a random double-blind fashion to the left and right sides of the upper part of the body for 60 days. In the first 30 days the medications were applied twice a day. Thereafter, during the second month, polyethylene occlusion for 48 hours with the medications was performed on the affected areas. Patients were assessed independently by two investigators. Evaluation was performed before treatment (baseline) and once a week. Lesions were rated for erythema, plaque thickness, extension, scales, and itching. The cyclosporine blood levels of each patient were monitored by both the radioimmunoassay (RIA) and the high-pressure liquid chromatography (HPLC) methods once a week in the first month and once a fortnight thereafter. In addition, routine hematology and renal blood function tests were performed. At the end of therapy as well as during the followup, there was no difference between the cyclosporinetreated lesions and those treated with olive oil. No improvement was noted at any of the treated sites of five patients; however, an exacerbation occurred in one patient. Results of routine blood tests were unchanged. All patients failed to show any signs of systemic absorption by either the RIA or the HPLC technique, which is specific for native cyclosporine. In a companion study of topical cyclosporine treatment in ten patients with alopecia areata, the RIA detected trace levels (67, 97 ng/ml) in blood samples from two patients. However, the RIA method is less specific and probably not as effective for detection of low levels of blood cyclospofine when compared to HPLC, which gave negative results in all samples. The results of this study and a prior study of Griffiths et al3 may indicate the ineffectiveness of topical cyclosporine treatment in psoriasis. The lack of effect of topical cyclosporine treatment suggests the necessity for therapeutic blood levels of
Correspondence
379
this drug to control the psoriatic lesions. Alternatively, a topical preparation achieving epidermal penetration superior to that which we described, such as the propyl alcohol solution used by Parodi and Rebora,4 might give therapeutic results without systemic effects. The undetectable levels of the drug in the blood of our patients and previously reported patients 5 indicate minimal absorption of the drug through the skin. Notably, in patients responding to low-dose systemic therapy, measurable blood levels of cyclosporine were found.~ Finally Kato et al 6 recently provided in vitro evidence for a lack of direct effect of cyclosporine on epidermal cell growth. This further supports a systemic immunologic mechanism for the drug in psoriasis.
A. Gilhar, M.D.,* G. Winterstein, M.D.,* and D. T. Golan, M.D.** Rebecca Sieff Hospital, Safed,* Haifa Medical Center (Rothchild ), and Faculty of Medicine, Technion, Haifa,** Israel
REFERENCES 1. Griffith CEM, Powles AL, Leonard JN, et al. Clearance of psoriasis with low dose cyclosporine. Br Med J 1986;293:731-2. 2. Page EH, Wexler DM, Guenther LC. Cyclosporin A. J AM ACADDERMATOL1986;14:785-91. 3. Griffiths CEM, Powles AV, Baker BS. Topical cyclosporine and psoriasis. Lancet 1987;2:806. 4. Parodi A, Rebora A. Topical cyclosporine in alopecia areata. Arch Dermatol 1987;123:165. 5. Thomson RW, Aldridge RD, Sewell HF. Topical cyclosporine in alopecia areata and nickel contact dermatitis. Lancet 1986;2:971-2. 6. Kato N, Halprin KM, Taylor J. Cyclosporine A does not inhibit epidermal cell growth at therapeutic levels. J Invest Dermatol 1987;88:52-4.
Does adult T-cell leukemia/lymphoma belong to the cutaneous T-cell lymphoma category? To the Editor: Based on the finding that many lymphomatous malignancies with prominent cutaneous involvement are of T-cell origin, Edelson and his colleagues 1'2used the designation cutaneous T-cell lymphoma to unite the various conditions with the distinguishing clinical and cellular denominators of the primary cutaneous lymphomas. Cutaneous T-cell lymphoma constitutes a spectrum of disease that includes not only mycosis fungoides and S6zary syndrome, an erythrodermic variant of mycosis fungoides, but also other lymphoreticular neoplasms distinguished by apparent primary skin infiltration with neoplastic helper T cells. Proposal of this novel entity has brought us more extensive and fundamental understanding not only
380
Journal of the American Academy of Dermatology
Correspondence
T a b l e I. C o m p a r i s o n b e t w e e n cutaneous T-cell l y m p h o m a and adult T-cell l e u k e m i a / l y m p h o m a
Characteristics of tumor cells Geographic distribution
I Course
Skin manifestations
Phenotypes
In vitro function 1
Cutaneous T-cell lymphoma No endemic area
Chronic ~
MF: Erythematous, plaque, and tumor stages SS: Erythroderma
Helper/inducer T3 +, 4 +, 10Tac antigen -6
Help
Papules, plaques, tumors, and erythroderma
Helper/inducer T3 § 4 + , 10 + Tac antigen +
Suppression
Adult T-ceU leukemia/ lymphoma Southwest Japan, West Indies, and Southeastern United States
Acute
DNA: Deoxyribonucleicacid. 1. Assessed in the effect on polyclonal production of immunoglobulinsby pokeweedmitogen-stimulatedB cells. 2. --, Normal; 1', elevated. 3. - , Absent; +, present. 4. Some patients with cutaneous T-cell lymphoma in endemic areas in Japan are reported to be positive for antibody against HTLV-Iwithout apparent monoclonal integrations of the proviral deoxyribonucleic acid. 5. Cutaneous T-cell lymphomaoften evolves to a very aggressiveform. 6. Tac antigen indicates the interleukin-2 (IL-2) receptor. Some aggressive forms of HTLV-I-negativecutaneous T-cell lymphoma are Tacpositive. 7. Many cutaneous T-cell lymphomapatients have elevated lactic dehydrogenaselevels arising from the malignantT cells. 8. As many as 50% of adult T-cell leukemia/lymphomapatients are normocalcemJc.
of pathogenesis of cutaneous lymphoma but also of possible influence of the skin on maturation and differentiation of T ceils. Because of the broad spectrum of disease, however, the definition of cutaneous T-cell lymphoma seems to vary with the investigator. As a result, different types of cutaneous lymphomas with the helper T-ceU phenotype are included in cutaneous T-cell lymphoma, depending on how cutaneous T-cell lymphoma is defined. Adult T-cell leukemia/lymphoma is a lymphoreticular malignancy characterized by the presence of pleomorphic neoplastic cells of the mature T-cell phenotype? The disease is associated with a human retrovims designated human T-cell leukemia/lymphoma virus I (HTLV-I): Patients with adult T-ceU leukemia/lymphoma frequently develop variable skin lesions, ineluding small papules, plaques, and erythroderrna. Histologic evaluations reveal epidermotropism and Pautrier's microabscesses of tumor cells in two thirds of patients with cutaneous involvement. These findings have raised a controversial issue on the distinction of adult T-cell leukemia/lymphoma from cutaneous T-cell lymphoma: Among several points as depicted in Table I, the detection of HTLV-I infection seems to be the most important point of distinction between cutaneous T-cell
lymphoma and adult T-cell leukemia/lymphoma. This is because the presence of viral genome in malignant cells of adult T-cell leukemia/lymphoma indicates not only an aggressive course, providing an important guide for treatment and prognosis, but also infective nature of the disease as in acquired immunodeficiency syndrome. We consider that adult T-cell leukemia/lymphoma should not be included in the cutaneous T-cell lymphoma category. The proper definition of cutaneous T-ceU lymphoma and adult T-cell leukemia/lymphoma will warrant such distinction.
Masahiro Takigawa, M.D., Fumio Inoue, M.D., KeOi lwatsuki, M.D., and Mizuho Yamada, M.D. Hamamatsu University School of Medicine Hamamatsu 431-31 Japan REFERENCES 1. Edelson RL, Kirkpatrick CH, Shevach EM, et al. Preferential cutaneous infiltration by neoplastic thymusderived lymphocytes. Morphologie and functional studies. Ann Intern Med 1974;80:685-92. 2. Edelson RL. Cutaneous T cell lymphoma: mycosis fungoides, S6zary syndrome, and other variants. J AM ACAD D~RM~,'rOL 1980;2:89-106. 3. Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T cell leukemia: clinical and hematologic features of 16 cases. Blood 1977;50:481-92.
Volume 18 Number 2, Part 1 February 1988
Correspondence
381
Serum levels of 2 Monoclonal Alkaline phos- Lactic dehy- AntibodYagainstintegrationHTLV. ofl
Ca++l Ph",!ae I drogenase .TLV+'+ pro ralD. *' 7
t 8
1'
1'
+
+
4. Hinuma Y, Nagata K, Hanaoka M, et al. Antigen in an adult T-cell leukemia cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci USA 1981 ;78:6476-80. 5. Shimoyama M, Minato K, Saito H, et al. Comparison of clinical, morphologic and immunologic characteristics of adult T-cell leukemia/lymphoma and cutaneous T-cell lymphoma. Jpn J Clin Oncol 1979;9(suppl):357-72.
Fig. 1. Exudative erythematous patches and target lesions on the thighs and legs.
Erythema multiforme due to clofibrate
To the Editor: Erythema multiforme is a relatively common acute dermatosis characterized by distinct target lesions. Although a variety of etiologic factors have been implicated as precipitating erythema multiforme, there is no known provocative factor in about one half of the cases. Here we report a case of erythema multiforme due to clofibrate (ethyl c~-[parachlorophenoxy]isobutyrate, Deliva), which was confirmed by readministration test.
Case report. A 72-year-old woman was admitted to our clinic because of generalized pruritic erythematous eruption, general malaise, and fever of sudden onset. She had had mild hypertension and hyperlipidemia and had been given some hypotensive agents and clofibrate (750 mglday) for about 1 year. On the day when the eruption developed she stopped taking clofibrate on her own. On physical examination she looked ill and had a temperature of 38.5 ~ C. Extldative fresh red erythematous patches of various sizes were seen on the entire body and extremities. The extensor surfaces of the upper limbs exhibited several bullae, exudative erythematous macules, and so-called target lesions in which the center cleared, becoming cyanotic or purpuric (Fig. 1). The face and the distal parts of her limbs showed marked edema. Biopsy specimens obtained from a macular lesion on the fight thigh showed marked edema of the papillary dermis and lymphohistiocytic, patchy infiltration around the dilated small
vessels, with a moderate number of eosinophils in the upper to mid dermis (Fig. 2). Biopsy examination o f a bullous lesion disclosed subepidermal blister formation. Laboratory values were not remarkable except for strongly positive C-reactive protein ( 6 + ) . Lipid values were as follows: cholesterol, 232 mg/dl; [3-lipoprotein, 607 mg/dt; and triglyceride, 154 mg/dl. Four days after admission she became afebfile, and the rash and edema gradually disappeared over 17 days. After complete disappearance of the eruptions a test dose of 500 mg clofibrate was given with her consent. Thirty minutes after oral readministration of clofibrate she noted pruritic, erythematous maeules developing on her abdomen, buttocks, and limbs. A patch test with clofibrate showed negative findings. Photopatch test and photodrug test with clofibrate and 1% parachlorophenol (a precursor of clofibrate) also showed negative findings.
Comment. Clofibrate is used worldwide as a hypolipidemic agent. There have been only few reports of eruptions that occurred as an adverse side effect o f therapy with clofibrate. Cumming ~ reported a patient with acute renal failure and generalized erythematous rash due to clofibrate. Immunofluorescence studies suggested that the possible general hypersensitivity to clofibrate caused the renal failure and generalized rash. Clofibrate is produced from parachlorophenol by ad-