Pigmented lesions on the palms and soles during PUVA therapy

Pigmented skin lesions due to PUVA are well recognized. They include freckles, mottled skin, naevus spilus-like lesions and 'PUVA lentigines' (Kietzmann & Christophers, 1984). The PUVA lentigo appears to be common, occurring in up to 53% of patients (Rhodes, Stern & Melski, 1983). These discrete brown macules, 2–5 mm in diameter, may become very widespread, particularly in those patients who have had many PUVA treatments. They tend to spare the face and have not previously been reported on the palms or soles.
We have now seen three female patients who have developed pigmented lesions on their palms (and in one case also on the sole) whilst receiving long-term oral PUVA therapy for psoriasis. The lesions were of two types: ill-defined light grey-brown macules (histologically a freckle, with no increase in number of basal melanocytes), and discrete dark brown macules. The latter showed focal proliferation of dendritic melanocytes at the dermo-epidermal junction, with increased pigmentation throughout the epidermis and also in the superficial dermis. These lesions developed after a minimum of 70 PUVA treatments (over 18 months) in one case, but only appeared after 5 years' PUVA (330 treatments) in another.
Ultrastructural studies (Rhodes, Harrist & Momtaz, 1983) have demonstrated that the melanocytes in PUVA lentigines may show cytological atypia. PUVA lentigines may also persist for up to 2 years (and probably longer) after stopping PUVA. Patients undergoing prolonged PUVA therapy to the palms and soles should be warned about the possibility of developing pigmented lesions which may persist after cessation of therapy.     

Atypical pigmented lesions following extensive PUVA therapy

We report a 38-year-old woman with psoriasis who developed multiple atypical lentigines following psoralen photochemotherapy (PUVA). The lentigines first appeared 12 years ago, 3 years after she commenced intermittent PUVA treatment. New lesions continued to develop over the subsequent years with further photochemotherapy. Clinically, the lentigines were strikingly atypical, deeply pigmented, dark brown or black, large stellate macules. Histology of a representative lesion was consistent with a PUVA lentigo and no atypical melanocytes were seen. At present, a link between malignant melanoma and PUVA lentigines has not been established. Instead, limited evidence suggests that PUVA lentigines may be more closely linked with the risk of nonmelanoma skin cancer.     

Skin cancers or premalignant lesions occur in half of high-dose PUVA patients

Although treatment of psoriasis with psoralen and ultraviolet A (PUVA) is associated with a long-term risk of development of cutaneous squamous cell carcinoma (SCC), the role of PUVA alone is not established, as many patients in reported series had also received treatment with other carcinogens, such as superficial X-rays or arsenic. We have recalled and examined 54 of the 63 patients still alive who have had PUVA treatment in our department, and who have been exposed to a cumulative UVA dose greater than 2000 J/cm². None of the patients had been treated with superficial X-rays or arsenicals. Ten patients (19%) had developed SCC, and 25 (46%) had histologically atypical squamous keratoses arising at body sites similar to the carcinomas. The patients with SCC were significantly older at the start of PUVA treatment than those with keratoses alone. None of the 13% of patients without PUVA lentigines had keratoses or SCCs. These results show that high-dose PUVA treatment in the U.K., even when given alone, can frequently result in the development of SCC. Further malignancies are to be expected with continued follow-up of the patients with squamous keratoses. Absence of PUVA lentigines may be a useful indicator of a lower risk of PUVA malignancy.     

Psoralen plus ultraviolet A irradiation-induced lentigines arising in vitiligo: involvement of vitiliginous and normal appearing skin

Psoralen plus ultraviolet A irradiation (PUVA therapy) is commonly used for the management of vitiligo in which perifollicular repigmentation is the usual response pattern. However, excessive PUVA therapy may be associated with adverse effects. We report a case of generalized vitiligo that has been extensively treated with topical and systemic PUVA therapy for several years with the development of extensive and widespread stellate and irregularly shaped black and brown macules (lentigines). Interestingly, the lentigines were observed not only in the normally pigmented skin but also within the depigmented lesions that were lacking the perifollicular response pattern. The lesions developed in the exposed and unexposed skin areas. No evidence of skin malignancy was observed clinically and no melanocyte atypia was detected histopathologically. Cryotherapy may be used in the management of the lentigines; however, because of the extent of lesions this was impractical in our case.     

Cutaneous carcinoma and PUVA lentigines in Thai patients treated with oral PUVA

A total of 113 Thai patients who were treated with oral PUVA from 1979 to 1992 were examined for long-term cutaneous side effects of PUVA. Two psoriatic patients developed PUVA keratosis on non-sun-exposed areas. Both were skin type IV and had had phototherapy with UVB and sunlight previously. The total doses of UVA were 909 J/cm² and 242 J/cm² respectively. One psoriatic patient developed Bowen's disease. He had had a cumulative dose of UVA 2207 J/cm². He also had a past history of arsenic intake and phototherapy with UVB and sunlight. PUVA lentigines were seen in 58 patients (51.4%). It was associated with older age at starting PUVA, higher cumulative UVA dose and greater number of PUVA treatment. This study suggests that previous exposure to other risk factors is important for inducing skin cancer in populations with skin phototype III, IV and V treated with oral PUVA.     

Cryotherapy of PUVA lentigines

PUVA lentigines do not subside after discontinuation of photochemotherapy. Cryotherapy with liquid nitrogen was done on a small area in a patient who presented with numerous PUVA lentigines. Five years after this treatment, the PUVA lentigines had not returned. Cosmelically disturbing PUVA lentigines can be treated with cryotherapy.     

Skin carcinomas and treatment with photochemotherapy (PUVA)

A 3 1/2-year follow-up study of 198 patients treated with photochemotherapy (PUVA) revealed a total of 18 carcinomas developed in 11 patients. There were 12 basal cell carcinomas and 6 squamous cell carcinomas, localized mainly on non-sun-exposed areas. Furthermore 9 actinic keratoses were diagnosed in 8 patients. All patients with carcinomas had been exposed to at least one of the following possible risk factors; ionizing radiation, methotrexate (MTX), arsenic, topical nitrogen mustard, or had a history of skin carcinoma previous to PUVA therapy. No significant differences in accumulated UVA dose existed between patients with carcinoma or keratosis and patients without tumours. A subgroup of 38 psoriatics previously treated with MTX was compared with a control group of 101 psoriatics treated with MTX--but never with PUVA. The control group was matched for sex, age and presence of the risk factors: ionizing radiation, arsenic and history of carcinoma. The carcinoma incidence in the PUVA-MTX group was 9% and in the control group 11%. The difference was not significant (p = 0.9).     

Comparison of therapeutic efficacy of topical PUVA, oral etretinate, and combined PUVA and etretinate for the treatment of psoriasis and development of PUVA lentigines and antinuclear antibodies

Sixty-two and 38 psoriatic patients were treated with topical PUVA and combined etretinate and topical PUVA (Re-PUVA), respectively. In both groups, 50% of the patients showed initial recovery after 6 weeks and over 90% after 14 weeks. Re-PUVA was more effective than PUVA alone in obtaining complete clearance (p<0.05). To clear psoriasis in 50% of the patients, PUVA and Re-PUVA required 63 and 26 weeks, respectively. Furthermore, the integrated clearance rates after 70 weeks were 50% in PUVA and 63% in Re-PUVA. Each therapy showed a similar remission period; psoriasis recurred in 50% of the patients after 4 months. In addition, 17 patients were treated with oral etretinate, and Re-PUVA was found to be more effective than etretinate monotherapy. Another aim was to determine whether etretinate would inhibit the development of PUVA side effects. Adding etretinate failed to inhibit the production of PUVA lentigines but clearly suppressed antinuclear antibody (ANA) expression. Six of 56 patients treated with PUVA alone developed ANA during the treatment. In marked contrast (p=0.05), ANA was detected in none of 34 patients treated with Re-PUVA.     

Morphologic alterations of epidermal melanocytes and melanosomes in PUVA lentigines: a comparative ultrastructural investigation of lentigines induced by PUVA and sunlight

Ultrastructural studies were conducted in order to determine morphologic and functional differences in melanocytes and melanosomes in PUVA lentigines and solar lentigines, and light-protected buttock skin. Compared to melanocytes in solar lentigines from 7 subjects and light-protected buttock skin from 5 subjects (none of these subjects had received UV radiation therapy), melanocytes in PUVA lentigines from 6 subjects generally had longer and more numerous dendrites, and showed more active melanogenesis. Basal keratinocytes in PUVA lentigines had a significantly increased frequency of large, single melanosomes, and revealed significantly larger individual melanosomes within compound melanosomes. Other findings in some PUVA lentigines included the close apposition of Langerhans cells to melanocytes, and atypical nuclear, cytoplasmic and melanosomal alterations, including melanosomal pleomorphism and melanin macroglobules. The presence of relatively large and predominantly single melanosomes in basal keratinocytes of PUVA lentigines suggests more active melanogenesis and/or an irreversible somatic alteration. It will be important to determine the clinical course and ultrastructural findings of PUVA lentigines that persist long after PUVA is discontinued.     

Long-term results of topical PUVA in necrobiosis lipoidica

The aim of our study was to evaluate the long-term results of topical psoralen ultraviolet A (PUVA) in patients with necrobiosis lipoidica (NL), in whom conventional methods (pentoxifylline, vitamin E, tretinoin, and topical or intralesional corticosteroids) had failed. The study comprised 10 women (age range 17-44 years), six of whom were insulin-dependent diabetics and four were diabetes-free. Duration of NL ranged from 3 to 10 years. The patients were treated with a 0.005% aqueous solution of 8-methoxypsoralen, applied topically for 30 min, and subsequently irradiated with UVA three times weekly. All the patients experienced almost complete remission (softening of skin lesions, no hyperpigmentation, lack of lesion progression) after a mean of 47 sessions (mean UVA cumulative dose 69.5 J/cm2). They were followed up for 12-24 months, during which time two recurrences, both in diabetic patients, were observed after 8 and 12 months of treatment cessation, which further resolved after another course of topical PUVA. We conclude that topical PUVA is well tolerated by NL patients and may serve as an alternative therapeutic regimen.     

PUVA treatment of vitiligo: a retrospective study of 59 patients.

We have performed a retrospective study of 59 patients with vitiligo who received PUVA therapy from 1972 to 1986. Sixteen patients had generalized vitiligo and 43 vitiligo in four locations (focal vitiligo). In both groups there were repigmentation in 44% of the patients. Half of the repigmented patients had improved more than 50%. None developed hypertrichosis, actinic keratosis, lentigines, or skin cancer within the observation period. Regardless of the results of PUVA therapy half of the patients thought PUVA was an acceptable therapy.     

Is the combination of calcipotriol and PUVA effective in vitiligo?

OBJECTIVE: The objective was to compare the effectiveness of psoralen plus ultraviolet A (PUVA) and the combination of PUVA and topical calcipotriol in the treatment of vitiligo. BACKGROUND: There are several reports on the response rate of patients with vitiligo treated with the combination of PUVA and calcipotriol or calcipotriol alone. SUBJECTS AND METHODS: Twenty-two patients with generalized vitiligo were taken into the study. PUVA treatment was applied on a twice-weekly schedule. Calcipotriol cream was applied to one of the two symmetrical lesions of each patient twice daily. RESULTS: Our results showed that the addition of topical calcipotriol to PUVA treatment did not lead to a significant increase in response rate of patients with vitiligo compared with PUVA treatment alone.     

The persistent risk of genital tumors among men treated with psoralen plus ultraviolet A (PUVA) for psoriasis

BACKGROUND: In the general population, squamous cell carcinomas (SCCs) of the male genitalia are rare. Ten years ago, we documented a significant dose-dependent increase in the risk of malignant genital neoplasms among men treated with psoralen plus ultraviolet A (PUVA). Since that time, fewer cohort patients have used PUVA, and genital protection among PUVA users is likely to be frequent. OBJECTIVE: Our aim was to determine the incidence and risk factors for genital neoplasms since 1989 and risk factors for these neoplasms among patients treated with PUVA. METHODS: We conducted a prospective cohort study of 892 men first treated with PUVA in 1975-1976. RESULTS: Twenty-four men (2.7%) had 51 genital neoplasms, including 10 patients with a first tumor after May 1, 1989 (the ending date for our 1990 report). Since May 1, 1989, the incidence of invasive penile and scrotal SCCs was elevated 52.6-fold (95% confidence interval, 19.3-114.6) compared with that expected for the general white population. Multivariate models revealed the highest genital tumor risk among men with high-dose exposure to both PUVA and topical tar/ultraviolet B, with an incidence rate ratio of 4.5 (95% confidence interval, 1.3-16.1) compared with the low-dose exposure group. CONCLUSION: Although use of PUVA has decreased and genital shielding in our cohort has increased, the dose-dependent increase in the risk of genital tumors in men treated with PUVA has persisted. Particularly high risks occur among those with high-dose exposures to both PUVA and topical tar/ultraviolet B.     

Treatment of actinic prurigo with PUVA: mechanism of action

Five patients with actinic prurigo were treated twice weekly with PUVA. One area on the back was shielded from UVA throughout the 15-week treatment period. Before PUVA, all patients had increased erythemal sensitivity to UVA and showed abnormal augmentation of UVB erythema by topical indomethacin. After PUVA, all patients were free of photosensitive symptoms and skin that had been exposed to UVA showed normal erythemal responses. By contrast, the areas of skin that had been protected from UVA showed erythemal responses that were unchanged from pre-PUVA values. Augmentation of UVB erythema by topical indomethacin persisted, both on UVA exposed and UVA protected skin. These results show that, although PUVA is an effective treatment in actinic prurigo, it does not alter the underlying mechanism of photosensitivity. The protective effect is local and is due presumably to an increase in melanin pigmentation and epidermal thickness.     

PUVA treatment of erythrodermic and plaque type mycosis fungoides

Five patients with plaque type mycosis fungoides (MF) and five patients with erythrodermic MF responded favorably to oral psoralen photochemotherapy (PUVA). The mean total UVA irradiation dose was less for erythrodermic than for plaque type MF, but the mean number of treatments to achieve clearing was greater in the erythrodermic patients. Histologic examination at clearing revealed persistence of an inflammatory infiltrate in the lower dermis in most cases. Subsequent recurrent lesions in five patients revealed a more extensive dermal inflammatory infiltrate, although findings were not always diagnostic of MF due to a lack of epidermal involvement. Resumption of more intensive PUVA therapy again resulted in clinical clearing in all five patients. The follow-up period for six patients who received long-term PUVA maintenance ranged from 1 1/2 to 3 1/2 years. During PUVA therapy, five of ten patients developed epithelial malignancies or premalignancies, and one patient developed a malignant fibrous histiocytoma. Most of these patients had received prior treatment with electron beam and topical nitrogen mustard.     

Treatment of genito-anal lesions in inflammatory skin diseases with PUVA cream photochemotherapy: an open pilot study in 12 patients

BACKGROUND: Localized skin lesions of the genito-anal region such as in lichen sclerosus et atrophicus or in lichen planus are a burden for many patients, and therapeutic efforts, including therapies with potentially hazardous side-effects, are often unsatisfactory. Recently, PUVA bath photochemotherapy has been proven highly effective in the treatment of various inflammatory skin diseases, including localized scleroderma. Another form of topical PUVA therapy, 8-methoxypsoralen-containing cream or gel preparations, has been proven to be as effective as PUVA bath therapy for palmoplantar dermatoses. OBJECTIVE: We evaluated the clinical effects of PUVA cream photochemotherapy in patients with genital lesions of inflammatory skin diseases. METHODS: Twelve patients with lichen sclerosus et atrophicus, lichen planus, vulvar eczema and pruritus vulvae were included in the study. PUVA cream therapy was performed up to 4 times a week. RESULTS: PUVA cream photochemotherapy induced a significant clinical improvement of genital lesions in most patients, as revealed by clinical examination. Clinical improvement (reduction in size of lesions of erythema, and/or of pruritus) was achieved in most patients after 10-20 treatments and was reduced in patients that had only received 5-15 treatments. Cumulative doses ranged between 4.5 and 180 J/cm(2); all patients tolerated PUVA cream phototherapy well without any side-effects. CONCLUSION: PUVA cream phototherapy represents a highly effective therapy that should be further investigated as an alternative treatment for patients with genital lesions of inflammatory skin diseases.     

局部PUVA治疗白癜风的疗效观察

为了探讨局部PUVA治疗癜风的疗效,对80例白癜风患者进行局部PUVA治疗。结果表明经30次治疗后,总有效率为85.00%,其中125例（18.75%）患者痊愈。局限型白癜风有较好的疗效。疗效与病程相关,与皮肤光毒反应无关。     

Twenty-nail dystrophy treated with topical PUVA

A case of twenty-nail dystrophy treated with topical PUVA is described. The patient, a 19-year-old woman, had a 4-year history of a nail dystrophy involving all finger- and toe-nails. The finger-nail changes were treated with topical PUVA, dose 0.7-1.4 J/cm2 x 3/week. After 7 months excellent improvement was seen, while the untreated toe-nails were unaffected. A maintenance dose of 0.7 J/cm2 x 3/week was necessary to prevent recurrence. We suggest that topical PUVA is worth trying for the treatment of twenty-nail dystrophy.     

Phototoxic reactions to photoactive drugs in patients treated with PUVA

To determine the potentially adverse effects of photoactive medications taken in conjunction with oral methoxsalen photochemotherapy (PUVA) for psoriasis, we studied the incidence of phototoxic reactions in 1,125 patients treated with PUVA at 15 centers. During the initial (clearing) phase of PUVA therapy, patients using photoactive medications were no more likely to have diffuse delayed erythema than patients who did not use such medications. After clearing, patients 45 years of age or older who used photoactive drugs were 2.3 times as likely to discontinue PUVA therapy for at least one month owing to problems related to UV-induced burns than were those who did not use such drugs. Only 6% of patients older than 45 years who took photoactive medications had problems with phototoxicity sufficiently severe to contribute to permanent discontinuation of PUVA therapy.     

A comparison of psoralen plus ultraviolet A (PUVA) monotherapy,tacalcitol plus PUVA and tazarotene plus PUVA in patients with chronic plaque-type psoriasis

BACKGROUND: Numerous studies have shown that the additional administration of topical or systemic antipsoriatic agents might serve as an effective means to increase the efficacy of photochemotherapy [psoralen plus ultraviolet (UV) A (PUVA)] for psoriasis. OBJECTIVES: To compare the therapeutic response to tacalcitol plus PUVA, tazarotene plus PUVA and PUVA monotherapy in patients with chronic plaque-type psoriasis. In addition, we also assessed the duration of remission induced by each regimen and the tolerability of the two combination treatments. METHODS: Thirty-one patients with chronic plaque-type psoriasis were included in this observer-blinded, intrapatient comparison trial. PUVA treatment was given four times weekly. Additionally, tacalcitol ointment and 0.1% tazarotene gel were applied separately on two target areas once daily in the evening. At the onset of therapy and every 2 weeks thereafter the response to treatment was determined by the Psoriasis Severity Index score, which assesses the degree of erythema, infiltration and scaling of the psoriatic lesions. After complete or near complete clearing patients were followed-up until relapse. RESULTS: Twenty-four patients completed the study. The treatment requirements to induce complete or near complete clearing were significantly lower for both combination treatments than for PUVA monotherapy (P < 0.01). The median cumulative UVA dose and number of exposures were 30.6 J cm-2 (95% confidence interval, CI 22.5-71.2) and 14 (95% CI 11-16) for tacalcitol plus PUVA, 32.3 J cm-2 (95% CI 22.5-73.8) and 14 (95% CI 11-19) for tazarotene plus PUVA, and 37.0 J cm-2 (95% CI 29.5-83.9) and 16 (95% CI 14-22) for PUVA monotherapy. No difference between the three regimens was observed with regard to duration of remission. Adverse reactions occurred more often with 0.1% tazarotene than with tacalcitol but were in general mild and completely reversible upon using a lower concentration of 0.05% tazarotene. CONCLUSIONS: Tacalcitol ointment and tazarotene gel are both comparably effective in improving the therapeutic result of PUVA therapy in patients with chronic plaque-type psoriasis. Besides accelerating the treatment response, both agents, by virtue of their UVA dose-sparing effect, might also help to reduce possible long-term hazards of PUVA treatment.