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Immunosuppression-induced porokeratosis of Mibelli: complete regression of lesions upon cessation of immunosuppressive therapy
Journal of the European Academy of Dermatology and Venereology 5 (1995) 170-172
EISEVIER
JEADV
Case report
Immunosuppression-induced porokeratosis of Mibelli: complete regression of lesions upon cessation of immunosuppressive therapy L. Gilead *, D. Guberman, A. Zlotogorski, D.A. Vardy, S.N. Klaus Department of Dermatology, Hadassah University Hospital, P.O. Box 12000, Jerusalem 91120, Israel
Abstract Porokeratosis developing subsequent to immunosuppressive therapy is a common and well recognized phenomenon. A previously reported case of porokeratosis showed complete remission of the lesions following discontinuation of immunosuppression. A second example of porokeratosis is presented, in which lesions appeared 2 years after bone marrow transplantation, and completely regressed after immunosuppressive therapy was stopped. Keywords: Porokeratosis; Immunosuppressive therapy; Lesions, complete regression 1. Introduction Porokeratosis (PK) is an uncommon dermatosis characterized by the progressive enlargement of a cutaneous plaque surrounded by a hyperkeratotic rim. The pathognemonic hallmark of this dermatosis is the histological presence of a column of parakeratotic cells, the cornoid lamella, at the rim of the lesion [l]. There are 6 recognized variants of PK. These are shown in Table 1 together with their abbreviations. The association of PK and immunosuppression was first reported in 1974 [21. Since then, at least 50 additional cases of immunosuppression-in-
Corresponding author. Tel: 972-2-776366, Fax: 972-2431221/434434. l
duced porokeratosis (ISIP) have been reported. ISIP is now commonly accepted as a common and expected side-effect of immunosuppression. To date, however, there has been only one case report in which total remission of PK occurred subsequent to discontinuation of immunosuppressive therapy [31. We present a second case, suggesting that this phenomenon is not an isolated event.
2.
A 32 year old male presented with pruritic cutaneous lesions of recent onset, as well as a cauliflower-like growth on the shaft of his penis. Two years previously, he was diagnosed as having acute myeloblastic leukemia, for which he re-
0926-9959/95/$09.50 0 1995 Elsevier Science B.V. All rights reserved SSDI 0926-9959(95)00047-X
Case report
L. Gilead et al. /J. Eur. Acad. Dermatol. Venereal. 5 (1995) 170-172 Table 1 Classification of porokeratosis Localized forms Classic or plaque type porokeratosis of Mibelli Linear porokeratosis of Mibelli Punctate porokeratosis of Mibelli Disseminate forms Disseminated superficial porokeratosis Disseminated superficial actinic porokeratosis Porokeratosis plantaris, palmaris et disseminata
(PM) (LPM) (punctate PM) (DSP) OX@) (PPPD)
ceived an allogeneous bone marrow transplantation from his sister some six months after diagnosis. One month after the bone marrow transplant, he developed an acute graft-versus-host disease (GVHD), and was consequently treated with high-dose corticosteroids and cyclosporine A. At the time of presentation, his GVHD was well controlled on daily oral doses of 30 mg prednisone and 150 mg cyclosporine A. Examina-
171
tion of his skin revealed three types of lesions. Numerous, umbilicated, flesh-colored papules, l-4 mm in diameter, were evenly distributed over the trunk, thighs, arms and neck. These were compatible with a diagnosis of molluscum contagiosum. A second type of lesion, a fleshy cauliflower-like growth with a diameter of 1.5 cm, was located on the dorsal aspect of the penile shaft, and was diagnosed as condyloma accuminata. The third type of lesion comprised round, erythematous plaques on the inner aspect of the right upper thigh (Fig. 11, the left buttock, and the posterior aspect of the left flank. These lesions showed central atrophy and a distinct peripheral horny border. A biopsy of this lesion (Fig. 2) confirmed the clinical diagnosis of PK. The penile lesion was successfully treated with topical podophyllotoxin, however, despite monthly cryosurgical treatments for the molluscum contagiosum and PK, new crops of both types of lesions continued to appear, predominantly on the patient’s arms and back.
Fig. 1. A lesion of porokeratosis found on the medial aspect of the proximal right thigh with the biopsy site on its border. Fig. 2. An H&E stained histological section taken from the lesion in Fig. 1 showing a typical cornoid lamella characteristic of porokeratosis.
172
L. Gilead et al. /J. Eur. Acad. Dermatol. Venereol. 5 (1995) 170-I 72
During the subsequent year, the dosage of immunosuppressive therapy was gradually reduced, resulting in immediate regression of the PK and molluscum contagiosum lesions. Two months after stopping the immunosuppression, the lesions had totally disappeared. Observations over the subsequent 14 months revealed no recurrence of either type of lesion. 3. Discussion
PK is widely believed to be an autosomal dominant disorder with incomplete penetrance [4,5], although the vast majority of reported cases of PK and ISIP are sporadic and are probably the result of new somatic mutations [61. In view of the common histological features, it has been suggested that all the varieties of PK result from a common mechanism, namely the expansion of an abnormal epidermal clone [7]. The wide range of clinical presentations, however, casts doubt on whether a single gene locus is responsible. Furthermore, the association of PK with immunosuppression cannot be solely explained on the basis of a single genetic factor. It is thus suggested that the expression of PK results from a localized or generalized impairment of immune surveillance [8]. Such impairment may be induced by either genetic or nongenetic triggers such as sun exposure (as in DSAP), trauma (the Koebner phenomenon as in PK), viral infection, or immunosuppression itself. Impaired immune surveillance may thus permit an abnormal epidermal clone to lose its proliferation control, resulting in the clinical appearance of PK. It is further suggested that in PK, a specific subtype of keratinocytes which normally expand in a specific pattern in the epidermis is the source of the abnormal epidermal clone. While the loss of proliferation control in one common subtype of keratinocytes results in solar keratosis, the loss of proliferation control in another, less common subtype may result in PK. This also may explain the generally conserved characteristic fitures of PK despite the wide range of clinical presentations. Such a hypothesis would account for the many
cases of ISIP now being reported, especially in the era of organ transplantations and iatrogenic immunosuppression. Further support for this hypothesis may be seen from the following: (a) Malignant degeneration in PK was first noted in 1942 [81, and many such cases have subsequently been reported. It is well known that cutaneous malignant transformation is associated with an impairment of immune surveillance [9,10]. (b) This case report, as well as the case of Tsambaos and Spiliopoulos [3], in which PK was induced by immunosuppression and cleared on cessation of immunosuppression, suggest a direct relationship between PK and immunosuppression. In summary, it appears likely that the prime defect in PK is an impairment of immune surveillance rather than a genetic disorder. This, however, requires further investigation. References
111Lever WF, Schaumburg-Lever G. Congenital diseases (genodermatoses). In Lever WF, Schaumburg-Lever G, editors: Histology of the skin, 6rh ed. Philadelphia, J.B. Lippincott Co. pp. 1983;62-64. PI MacMillan AL, Roberts SOB. Porokeratosis of Mibelli after renal transplantation. Br J Dermatol 1983;90:45-51. [31 Tsambaos D, Spiliopoulos T. Disseminated superficial porokeratosis: Complete remission subsequent to discontinuation of immunosuppression. J Am Acad Dermatol 1993;28:651-652. [41 Gilchrist TC. Eleven cases of porokeratosis (Mibelli) in one family. J Cutan Genitourin Dis 1899;17:149. 151Anderson DE, Chemosky ME. Disseminated superficial actinic porokertosis: Genetic aspects. Arch Dermatol 1969;99:408-412. [61Larregue M, Prigent F, Lorette G, Canuel C, Titi M, Champipio R, Alcalay D. Porokeratosis de Mibelli chez deux jumeaux monozygotes. Ann Dermatol Venereol 1981;108:151-156, [71 Reed RJ, Leone P. Porokeratosis: A mutant clonal keratosis of the epidermis. Arch Dermatol1970;101:340-347. [81 Manganoni AM, Facchetti F, Gavazzoni R. Involvement of epidermal langerhans cells in porokeratosis of immunosuppressed renal transplant recipients. J Am Acad Dermatol 1989;21:799-801. [91 Vigne P, Porokeratosis de Mibelli: Trois cas familiaux, Transformation neoplastigae chez l’an d’eux. Anna1 Dermatol Syphiligr Paris 1942;2:5-15. 1101Abel AA. Cutaneous manifestaions of immunosuppression in organ transplant recipients. J Am Acad Dermatol 1989;21:167-79.
EISEVIER
JEADV
Case report
Immunosuppression-induced porokeratosis of Mibelli: complete regression of lesions upon cessation of immunosuppressive therapy L. Gilead *, D. Guberman, A. Zlotogorski, D.A. Vardy, S.N. Klaus Department of Dermatology, Hadassah University Hospital, P.O. Box 12000, Jerusalem 91120, Israel
Abstract Porokeratosis developing subsequent to immunosuppressive therapy is a common and well recognized phenomenon. A previously reported case of porokeratosis showed complete remission of the lesions following discontinuation of immunosuppression. A second example of porokeratosis is presented, in which lesions appeared 2 years after bone marrow transplantation, and completely regressed after immunosuppressive therapy was stopped. Keywords: Porokeratosis; Immunosuppressive therapy; Lesions, complete regression 1. Introduction Porokeratosis (PK) is an uncommon dermatosis characterized by the progressive enlargement of a cutaneous plaque surrounded by a hyperkeratotic rim. The pathognemonic hallmark of this dermatosis is the histological presence of a column of parakeratotic cells, the cornoid lamella, at the rim of the lesion [l]. There are 6 recognized variants of PK. These are shown in Table 1 together with their abbreviations. The association of PK and immunosuppression was first reported in 1974 [21. Since then, at least 50 additional cases of immunosuppression-in-
Corresponding author. Tel: 972-2-776366, Fax: 972-2431221/434434. l
duced porokeratosis (ISIP) have been reported. ISIP is now commonly accepted as a common and expected side-effect of immunosuppression. To date, however, there has been only one case report in which total remission of PK occurred subsequent to discontinuation of immunosuppressive therapy [31. We present a second case, suggesting that this phenomenon is not an isolated event.
2.
A 32 year old male presented with pruritic cutaneous lesions of recent onset, as well as a cauliflower-like growth on the shaft of his penis. Two years previously, he was diagnosed as having acute myeloblastic leukemia, for which he re-
0926-9959/95/$09.50 0 1995 Elsevier Science B.V. All rights reserved SSDI 0926-9959(95)00047-X
Case report
L. Gilead et al. /J. Eur. Acad. Dermatol. Venereal. 5 (1995) 170-172 Table 1 Classification of porokeratosis Localized forms Classic or plaque type porokeratosis of Mibelli Linear porokeratosis of Mibelli Punctate porokeratosis of Mibelli Disseminate forms Disseminated superficial porokeratosis Disseminated superficial actinic porokeratosis Porokeratosis plantaris, palmaris et disseminata
(PM) (LPM) (punctate PM) (DSP) OX@) (PPPD)
ceived an allogeneous bone marrow transplantation from his sister some six months after diagnosis. One month after the bone marrow transplant, he developed an acute graft-versus-host disease (GVHD), and was consequently treated with high-dose corticosteroids and cyclosporine A. At the time of presentation, his GVHD was well controlled on daily oral doses of 30 mg prednisone and 150 mg cyclosporine A. Examina-
171
tion of his skin revealed three types of lesions. Numerous, umbilicated, flesh-colored papules, l-4 mm in diameter, were evenly distributed over the trunk, thighs, arms and neck. These were compatible with a diagnosis of molluscum contagiosum. A second type of lesion, a fleshy cauliflower-like growth with a diameter of 1.5 cm, was located on the dorsal aspect of the penile shaft, and was diagnosed as condyloma accuminata. The third type of lesion comprised round, erythematous plaques on the inner aspect of the right upper thigh (Fig. 11, the left buttock, and the posterior aspect of the left flank. These lesions showed central atrophy and a distinct peripheral horny border. A biopsy of this lesion (Fig. 2) confirmed the clinical diagnosis of PK. The penile lesion was successfully treated with topical podophyllotoxin, however, despite monthly cryosurgical treatments for the molluscum contagiosum and PK, new crops of both types of lesions continued to appear, predominantly on the patient’s arms and back.
Fig. 1. A lesion of porokeratosis found on the medial aspect of the proximal right thigh with the biopsy site on its border. Fig. 2. An H&E stained histological section taken from the lesion in Fig. 1 showing a typical cornoid lamella characteristic of porokeratosis.
172
L. Gilead et al. /J. Eur. Acad. Dermatol. Venereol. 5 (1995) 170-I 72
During the subsequent year, the dosage of immunosuppressive therapy was gradually reduced, resulting in immediate regression of the PK and molluscum contagiosum lesions. Two months after stopping the immunosuppression, the lesions had totally disappeared. Observations over the subsequent 14 months revealed no recurrence of either type of lesion. 3. Discussion
PK is widely believed to be an autosomal dominant disorder with incomplete penetrance [4,5], although the vast majority of reported cases of PK and ISIP are sporadic and are probably the result of new somatic mutations [61. In view of the common histological features, it has been suggested that all the varieties of PK result from a common mechanism, namely the expansion of an abnormal epidermal clone [7]. The wide range of clinical presentations, however, casts doubt on whether a single gene locus is responsible. Furthermore, the association of PK with immunosuppression cannot be solely explained on the basis of a single genetic factor. It is thus suggested that the expression of PK results from a localized or generalized impairment of immune surveillance [8]. Such impairment may be induced by either genetic or nongenetic triggers such as sun exposure (as in DSAP), trauma (the Koebner phenomenon as in PK), viral infection, or immunosuppression itself. Impaired immune surveillance may thus permit an abnormal epidermal clone to lose its proliferation control, resulting in the clinical appearance of PK. It is further suggested that in PK, a specific subtype of keratinocytes which normally expand in a specific pattern in the epidermis is the source of the abnormal epidermal clone. While the loss of proliferation control in one common subtype of keratinocytes results in solar keratosis, the loss of proliferation control in another, less common subtype may result in PK. This also may explain the generally conserved characteristic fitures of PK despite the wide range of clinical presentations. Such a hypothesis would account for the many
cases of ISIP now being reported, especially in the era of organ transplantations and iatrogenic immunosuppression. Further support for this hypothesis may be seen from the following: (a) Malignant degeneration in PK was first noted in 1942 [81, and many such cases have subsequently been reported. It is well known that cutaneous malignant transformation is associated with an impairment of immune surveillance [9,10]. (b) This case report, as well as the case of Tsambaos and Spiliopoulos [3], in which PK was induced by immunosuppression and cleared on cessation of immunosuppression, suggest a direct relationship between PK and immunosuppression. In summary, it appears likely that the prime defect in PK is an impairment of immune surveillance rather than a genetic disorder. This, however, requires further investigation. References
111Lever WF, Schaumburg-Lever G. Congenital diseases (genodermatoses). In Lever WF, Schaumburg-Lever G, editors: Histology of the skin, 6rh ed. Philadelphia, J.B. Lippincott Co. pp. 1983;62-64. PI MacMillan AL, Roberts SOB. Porokeratosis of Mibelli after renal transplantation. Br J Dermatol 1983;90:45-51. [31 Tsambaos D, Spiliopoulos T. Disseminated superficial porokeratosis: Complete remission subsequent to discontinuation of immunosuppression. J Am Acad Dermatol 1993;28:651-652. [41 Gilchrist TC. Eleven cases of porokeratosis (Mibelli) in one family. J Cutan Genitourin Dis 1899;17:149. 151Anderson DE, Chemosky ME. Disseminated superficial actinic porokertosis: Genetic aspects. Arch Dermatol 1969;99:408-412. [61Larregue M, Prigent F, Lorette G, Canuel C, Titi M, Champipio R, Alcalay D. Porokeratosis de Mibelli chez deux jumeaux monozygotes. Ann Dermatol Venereol 1981;108:151-156, [71 Reed RJ, Leone P. Porokeratosis: A mutant clonal keratosis of the epidermis. Arch Dermatol1970;101:340-347. [81 Manganoni AM, Facchetti F, Gavazzoni R. Involvement of epidermal langerhans cells in porokeratosis of immunosuppressed renal transplant recipients. J Am Acad Dermatol 1989;21:799-801. [91 Vigne P, Porokeratosis de Mibelli: Trois cas familiaux, Transformation neoplastigae chez l’an d’eux. Anna1 Dermatol Syphiligr Paris 1942;2:5-15. 1101Abel AA. Cutaneous manifestaions of immunosuppression in organ transplant recipients. J Am Acad Dermatol 1989;21:167-79.