Photodynamic therapy for the treatment of extramammary Paget's disease

BACKGROUND: Surgical and ablative treatment modalities for extramammary Paget's disease (EMPD) have high recurrence rates and can be associated with significant morbidity. OBJECTIVES: To evaluate photodynamic therapy (PDT) for the treatment of EMPD. METHODS: We conducted a retrospective review of notes and histology of five men with anogenital, groin and axillary EMPD treated with PDT at Roswell Park Cancer Institute between 20 April 1995 and 1 February 2001. RESULTS: Sixteen EMPD lesions were treated with topical aminolaevulinic acid (ALA)-PDT. Eleven of these lesions had failed previous Mohs micrographic surgery, excision or laser ablation. When evaluated 6 months after one treatment with ALA-PDT, eight of 16 (50%) sites achieved a complete clinical response (CR); six of eight CRs were in lesions that had failed prior conventional therapies. Three of the eight CRs (37.5%) recurred at 9, 10 and 10 months. One patient who was partially responsive to topical ALA-PDT subsequently received systemic Photofrin(R)-PDT, with a complete clinical and histological response at 1 year. Functional and cosmetic outcome was excellent in all patients. CONCLUSIONS: PDT is an effective treatment for EMPD. Recurrence rates are high with topical ALA-PDT, but comparable with standard therapies. Topical ALA-PDT causes little scarring and is preferred for superficial disease and mucosal surfaces. Systemic Photofrin(R)-PDT may be better suited for bulky disease. While further studies are indicated, PDT is well tolerated and appears to be a useful therapy for EMPD.     

Spontaneous apparent clinical resolution with histologic persistence of a case of extramammary Paget's disease: response to topical 5-fluorouracil

An 86-year-old woman presented with a 3-year history of an erythematous axillary lesion, which was histologically confirmed to be extramammary Paget's disease (EMPD) confined to the epidermis and adnexa. Surprisingly, spontaneous clinical regression occurred in the lesion, but Paget's cells persisted within the epidermis and adnexa on histologic examination. One year of intermittent topical chemotherapy with 5-fluorouracil resulted in ulcers that were interpreted as EMPD and completely excised. Histologic examination showed a complete absence of Paget's cells. To our knowledge, only one previous report investigated apparent spontaneous clinical resolution with histologic persistence of EMPD. We emphasize that topical 5-fluorouracil cannot be considered a safe treatment modality for EMPD, but it may be useful in certain cases in which the extent of the lesions, or the general condition of the patient, advise against surgery or radiotherapy.     

Incomplete efficacy of 5-aminolevulinic acid (5 ALA) photodynamic therapy in the treatment of widespread extramammary Paget's disease

Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is an effective treatment for several conditions such as Bowen's disease, subsets of basal cell carcinomas and actinic keratosis. Surgical resection is the first-choice therapy for extramammary Paget's disease (EMPD), but extensive resection is highly invasive and recurrences are frequent. We report two cases of genital EMPD treated by PDT with partial efficacy. The first patient, a 78-year-old male, suffered from pubic and scrotal Paget's disease for 6 years despite numerous treatments. The second patient, a 78-year-old female, had vulvar involvement for 2 years that was resistant to multiple treatments. The disease was recurrent and chronic with important pruritus and significant impact on the quality of life. Methyl 5-aminolevulinate was applied for 3 h, and irradiation was applied with red light (630 nm) using a total light dose of 37 J/cm(2) for a period of 10 min. The patients were treated every 2 to 4 weeks for a total of at least three treatments. Both patients experienced a partial transient reduction in their symptoms. One patient had a partial transient remission (< 50% reduction of the involved surface), whereas in the other patient, PDT failed to reduce the surface area of the lesions.     

Topical 5-aminolaevulinic acid-photodynamic therapy for the treatment of urethral condylomata acuminata

BACKGROUND: Electrocoagulation and laser evaporation for urethral condylomata acuminata have high recurrence rates and can be associated with urethral malformations. OBJECTIVES: To investigate the effect of photodynamic therapy (PDT) with topical 5-aminolaevulinic acid (ALA) on urethral condylomata acuminata and to examine the histological changes in lesions of condylomata acuminata after ALA-PDT. METHODS: Patients with urethral condylomata (n = 164) were given topical ALA followed by intraurethral PDT through a cylindrical fibre. Patients included 11 individuals with 16 penile or vulval condylomatous lesions which were biopsied before or after treatment; the histological changes were then evaluated by light microscopy and electron microscopy. RESULTS: The complete response rate was 95% and the recurrence rate was 5% after 6-24 months of follow-up. Light microscopy revealed keratinocytes in the middle and upper layers of the epidermis showing marked vacuolation and some necrocytosis 1 and 3 h after PDT. Necrosis in all layers of the epidermis was noted 5 h after PDT. Electron microscopy of keratinocytes revealed distinct ultrastructural abnormalities of mitochondria and the endoplasmic reticulum, and membrane damage. Apoptotic bodies were detected 3 h after PDT and a large number of keratinocytes exhibited necrosis 5 h after PDT. CONCLUSIONS: Results suggest that, compared with conventional therapies, topical ALA-PDT is a simple, effective, safe and well-tolerated treatment for urethral condylomata acuminata that is associated with a low recurrence rate. The mechanism might be the triggering of both apoptosis and necrosis by ALA-PDT in human papillomavirus-infected keratinocytes.     

Extramammary Paget's disease of the genitalia with clinically clear margins can be adequately resected with 1 cm margin

For the treatment of extramammary Paget's disease (EMPD), wide excision has been recommended because of unpredictable spread of tumor cells. EMPD lesions are often well circumscribed. Should all the lesions of EMPD be resected with a 3 cm margin? Forty-six patients with EMPD were surgically treated with a 1 cm margin. Width of tumor cell free area from the last lesional cells at the borders to the resected edge was measured with micro-oculometer. The microscopic gap between the histopathological tumor border and the clinical border scored by scalpel tract was also measured. The tumor cell free area measured 10.2 +/- 2.48 mm. The microscopic gap between the histopathological and clinical borders measured 0.334 +/- 1.183 mm. Thus, the clinically determined border of well-defined lesions of EMPD corresponded well to the histopathologic border. No local recurrence was observed in 24 to 115 months of follow-up. Well-demarcated lesions of EMPD can be adequately managed with 1 cm margin resection.     

Treatment of limited extent extramammary Paget's disease with 5 percent imiquimod cream

Extramammary Paget's disease (EMPD) is a rare neoplastic condition of apocrine gland-bearing skin, which may be associated with internal malignancy. Although surgical excision is the generally accepted standard of care for EMPD, treatment with topical imiquimod 5 percent cream has reportedly been efficacious in clearing lesions. We report the case of a 78-year-old woman with biopsy-proven EMPD of the thigh treated successfully with imiquimod application thrice weekly for 16 weeks.     

Comparative study of photodynamic therapy vs CO2 laser vaporization in treatment of condylomata acuminata: a randomized clinical trial

BACKGROUND: Most conventional therapies for condylomata acuminata (CA) are traumatic and have high recurrence rates. OBJECTIVES: To investigate the efficacy and safety of topical application of 5-aminolaevulinic acid (ALA) photodynamic therapy (PDT) for the treatment of CA. METHODS: Sixty-five patients with CA were allocated into the treatment (ALA-PDT) group and treated with 20% ALA solution under occlusive dressing for 3 h followed by irradiation with the helium-neon laser at a dose of 100 J cm(-2) and a power of 100 mW. Another 21 CA patients were allocated into the control group and treated with the CO(2) laser. The treatment was to be repeated 1 week later if the lesion was not completely removed after the first treatment. RESULTS: After one treatment, the complete removal rate was 95% in the ALA-PDT group and 100% in the control group. After two treatments with ALA-PDT, the complete removal rate in the treatment group was 100%. The recurrence rate for ALA-PDT group was 6.3% which was significantly lower than that in control group (19.1%, P < 0.05). Moreover, the proportion of patients with adverse effects in the ALA-PDT group (13.9%) was also significantly lower than that in control group (100%, P < 0.05). The side-effects in patients treated with ALA-PDT mainly included mild burning and/or stinging restricted to the illuminated area. CONCLUSIONS: The present study shows that topical application of ALA-PDT is a simpler, more effective and safer therapy with a lower recurrence for treatment of CA compared with conventional CO(2) laser therapy.     

Successful treatment of lymphadenosis benigna cutis with topical photodynamic therapy with delta-aminolevulinic acid

BACKGROUND: Photodynamic therapy (PDT) using topical delta-aminolevulinic acid (ALA) has been used for nonmelanoma skin cancers, including malignant cutaneous T-cell lymphomas. Moreover, PDT has been tried for benign inflammatory or infectious skin lesions. OBJECTIVE: To evaluate the effects of ALA-PDT on skin lesions of lymphadenosis benigna cutis (LABC). PATIENTS AND METHODS: Two 16-year-old females with solitary and infiltrated nodules were treated 5 times with topical ALA-PDT. RESULTS: Both patients responded well and showed dramatic clinical and histopathological improvement without visible scars. CONCLUSION: The results confirm that topical ALA-PDT is an effective and safe modality for the treatment of LABC, and that such treatment may be cosmetically beneficial.     

ALA光动力治疗鲍温样丘疹病临床研究

目的观察5氨基酮戊酸(5aminolevulinicacid,ALA)光动力疗法(photodynamictherapy,PDT)治疗鲍温样丘疹病的临床疗效。方法治疗组38例采用ALAPDT治疗,每周治疗1次,共治疗4次;对照组15例予以二氧化碳激光治疗。结果治疗组痊愈12例,显效12例,有效率为61.2%,复发2例,复发率16.7%,无明显疼痛、创面等副作用;对照组痊愈9例,显效3例,有效率为80.0%,复发5例,复发率55.5%,15例均有术后明显创面疼痛,8例合并创面感染,9例出现表浅瘢痕。两组之间有效率和复发率无显著性差异(P>0.05)。结论ALAPDT是治疗鲍温样丘疹病的一种安全、有效、无明显痛苦和不良反应的新疗法。     

Non-oncologic indications for ALA-PDT

Topical photodynamic therapy with 5-aminolevulinic acid (ALA-PDT) is a well-established treatment regimen for superficial epithelial skin tumours, but it is evident that inflammatory diseases of the skin and virus-induced lesions can also profit from PDT. Depending on the light dose applied, either cytotoxic effects resulting in tumour destruction or immunomodulatory effects resulting in improvement of inflammatory conditions occur. Patients with localized scleroderma that had been unresponsive to various treatments, including PUVA or bath-PUVA therapy, respond very well to topical ALA-PDT performed repeatedly. In contrast to PUVA therapy, no carcinogenic potential is being discussed for PDT. Also, HPV-induced skin lesions might provide a possible indication for topical ALA-PDT. The rapidly proliferating cells in viral acanthomas accumulate ALA-induced protoporphyrin IX (PPIX) selectively when compared to the surrounding non-infected cells. The efficacy of topical ALA-PDT in the treatment of recalcitrant foot and hand warts has been shown in a placebo-controlled, randomized, double-blind trial. Furthermore, case reports describe a good response of other virus-induced diseases, for example condylomata acuminata and epidermodysplasia verruciformis, to topical PDT with ALA. However, controlled clinical trials are still needed to demonstrate more fully the effectiveness of PDT for inflammatory skin diseases.     

Extramammary Paget's disease resistant to surgery and imiquimod monotherapy but responsive to imiquimod combination topical chemotherapy with 5-fluorouracil and retinoic acid: a case report

Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm that usually affects the elderly population and occurs in the genital, anorectal, or axillary areas. The recommended treatment of EMPD involves surgical excision, including Mohs micrographic surgery; however, surgery is associated with a high rate of recurrence. There have been reports of successful treatment of recurrence with monochemotherapy involving topical imiquimod 5% cream. We report a case of EMPD recurrence after surgery that was resistant to imiquimod monotherapy but that completely resolved after imiquimod was combined with topical 5-fluorouracil (5-FU) and retinoic acid. To our knowledge, this is the first reported case of imiquimod combination therapy with 5-FU and retinoic acid for the treatment of recurrent EMPD.     

Extramammary Paget''s disease:

We examined 32 cases (38 lesions) of extramammary Paget's disease (EMPD) in relation to comparative studies on intraductal carcinoma of the breast (ductal carcinoma in situ, DCIS) and apocrine adenocarcinoma (AAC). Lesions included scrotum (18 lesions), vulva (8), axilla (6), groin (3), penis (2) and chest wall (1), and the distribution was compatible with that of apocrine or supernumerary mammary glands. Histologically, extra-mammary Paget's and DCIS cells exhibited a large amount of a pale-stained cytoplasm. The cytoplasm of AAC cells frequently contained granules, was eosinophilic and differed from that of Paget's or DCIS cells. Immunohistochemical studies revealed positive reactions for polyclonal and monoclonal antibodies to carcinoembryonic antigen in all EMPD and most DCIS, but not in AAC. Recent studies have shown that extramammary Paget's cells exhibit characteristics of glandular epithelial cells and that most cases of EMPD are not accompanied by an underlying carcinoma. The results obtained in this study, coupled with data on the frequency of the supernumerary breasts, lead to the speculation that extramammary Paget's cells originate from ectopic mammary glands or from pluripotential germinative cells in the epidermis, capable of differentiating toward the mammary glands.     

Irradiance and light dose influence histological localization of photodamage induced by photodynamic therapy with aminolaevulinic acid

BACKGROUND: Photodynamic therapy (PDT) with aminolaevulinic acid (ALA) is used in many countries for the treatment of actinic keratoses. OBJECTIVES: The objectives of the current study were to evaluate the influence of irradiance and light dose on the localization and extent of photodamage to mouse skin following ALA-PDT. METHODS: In this study we evaluated the influence of irradiance and light dose on epidermal photodamage following ALA-PDT. Groups of hairless mice received an intraperitoneal injection of ALA followed 2 h later by exposure to 12 J cm(-2), 24 J cm(-2) or 48 J cm(-2) of unfiltered light from a slide projector. For each of these fluences, groups of mice were exposed at the following irradiances: 5 mW cm(-2), 20 mW cm(-2) or 40 mW cm(-2). Skin biopsies were performed 24 h and 72 h later. RESULTS: Histological localization of photodamage was influenced by irradiance and light dose. At high irradiance and low fluence, PDT photodamaged cells were mostly located in the upper area of the epidermis whereas at lower irradiance and high fluence the complete epidermis was necrotic and often absent 24 h after light exposure. Protoporphyrin IX (PpIX) fluorescence intensity was similar in the upper and lower region of the epidermis 2 h after ALA injection. The decrease in PpIX fluorescence intensity immediately after light exposure was also similar in both regions of the epidermis. CONCLUSIONS: The localization of photodamage following ALA-PDT is influenced by irradiance and light dose. This phenomenon cannot be explained by differences in PpIX intensity in the epidermis either before or after light exposure.     

Mohs显微手术治疗乳房外Paget病42例

目的:评价Mohs治疗乳房外Paget病的疗效。方法:42例乳房外Paget病患者沿皮损周围2 cm行Mohs手术切除,确认边缘结果阴性之后行皮瓣或植皮闭合。术后31例患者使用光动力,每周1次,共4次。11例外用咪喹莫特乳膏,每日1次,共半年,随访8~36个月。结果:6例患者复发,复发率14.3%,其中4例为术后光动力治疗患者,2例为术后外用咪喹莫特乳膏。结论:EMPD进行Mohs显微描记手术结合光动力治疗或外用咪喹莫特乳膏有效。     

Extramammary Paget's disease/carcinoma successfully treated with a combination chemotherapy: report of two cases

We have treated two patients with extramammary Paget's disease/carcinoma (EMPD/C), a 62-year-old woman and a 78-year-old man. In both patients, lymph nodes in the areas of the bilateral inguinal, external iliac arteries, and abdominal aorta were affected. After surgery, they underwent 5 courses of systemic combination chemotherapy at 4-week intervals to residual or recurrent lymph node metastasis. Each course consisted of 3.5 mg mitomycin C and 50 mg epirubicin (day 1), 0.6 mg vincristine (days 1 and 7), 30 mg cisplatin (days 1, 2, and 3), and 350 mg 5-fluorouracil (days 3, 4, 5, 6, and 7). The affected lymph nodes in both patients subsided in response to the chemotherapy. Positron emission tomography (PET) scans confirmed the complete remission of lymph node metastasis in Case 1. In Case 2, they were reduced by more than 90% on computed tomography (CT) scans. Adverse effects included leukocytopenia, vomiting, hypesthesia, and constipation, all of which disappeared after the completion of chemotherapy. While surgery with wide local excision is the treatment of choice in patients with EMPD/C, there is currently no standardized treatment for advanced cases with metastasis. We describe two patients with EMPD/C whose metastatic lesions responded well to this combination of chemotherapy.     

Topical aminolaevulinic acid‐based photodynamic therapy as a treatment option for psoriasis? Results of a randomized,observer‐blinded study

BACKGROUND: Topical aminolaevulinic acid-based photodynamic therapy (ALA-PDT) has recently been tried in small open studies for several inflammatory dermatoses including psoriasis. OBJECTIVES: The purpose of this randomized, within patient comparison study was to investigate whether topical ALA-based PDT using a range of light doses can induce a satisfactory response in localized psoriasis. PATIENTS AND METHODS: Twenty-nine patients with chronic plaque type psoriasis were enrolled in the study. After keratolytic pretreatment three psoriatic plaques in each patient were randomly allocated to PDT with 1% ALA and a light dose of 5 J cm(-2), 10 J cm(-2) or 20 J cm(-2), respectively. Treatment was performed twice weekly until complete clearance or for a maximum of 12 irradiations. As a measure of clinical response the psoriasis severity index (PSI) of the three target plaques was assessed separately by an observer blinded to the treatment at baseline, before each PDT treatment and 3-4 days after the last irradiation. RESULTS: Eight patients withdrew prematurely from the study. Keratolytic pretreatment alone reduced the baseline PSI in all three dose groups by about 25%. Subsequent PDT with 20 J cm(-2) resulted in a final reduction of PSI by 59%, PDT with the lower doses of 10 J cm(-2) and 5 J cm(-2) decreased the baseline PSI by 46% and 49%, respectively. The difference in clinical efficacy between 20 J cm(-2) and 10 J cm(-2) or 5 J cm(-2) was statistically significant (P = 0.003; P = 0.02), whereas no difference was found between 10 J cm(-2) and 5 J cm(-2) (P = 0.4). All patients reported some degree of PDT-induced stinging or burning during irradiation. CONCLUSIONS: The unsatisfactory clinical response and frequent occurrence of pain during and after irradiation renders topical ALA-based PDT an inadequate treatment option for psoriasis.     

Comparative Study of Photodynamic Therapy with Topical Methyl Aminolevulinate versus 5-Aminolevulinic Acid for Facial Actinic Keratosis with Long-Term Follow-Up

Background

Few studies have compared the efficacy, cosmetic outcomes, and adverse events between 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and methyl aminolevulinate-PDT (MAL-PDT) for actinic keratoses (AKs) in Asian ethnic populations with dark-skin.

Objective

We retrospectively compared the long-term efficacy, recurrence rates, cosmetic outcomes, and safety of ALA-PDT versus MAL-PDT for facial AKs in Koreans.

Methods

A total of 222 facial AKs in 58 patients were included in this study. A total of 153 lesions (29 patients) were treated with 5-ALA, and 69 lesions (29 patients) with MAL. ALA and MAL creams were applied for 6 hours and 3 hours, respectively; the lesions were then illuminated with a halogen lamp at 150 J/cm² for ALA-PDT and a diode lamp at 37 J/cm² for MAL-PDT.

Results

The complete response rates of ALA-PDT and MAL-PDT were 56.9% and 50.7%, respectively, with no significant difference at 12 months after treatment. No significant difference in recurrence rates was observed between the 2 PDT modalities at either 6 or 12 months after treatment. There was no significant difference in the cosmetic outcomes between the 2 treatment modalities at 12 months after PDT. However, ALA-PDT caused significantly more painful than MAL-PDT (p=0.005). The adverse events were mild to moderate, transient, and self-limiting for both modalities.

Conclusion

MAL-PDT was similar to ALA-PDT in terms of long-term efficacy, recurrence rates, cosmetic outcomes, and adverse events; however, it was a significantly less painful procedure than ALA-PDT in our study.     

Genital Paget's disease with clear cells in the epidermis of the axilla

We report an 84-year-old man with extramaminary Paget's disease (EMPD) involving the genital region. Microscopic examination revealed very few clear cells appearing pagetoid in the lower portion of prickle cell layer of the right axilla epidermis, with no clinically detectable eruption. Their histochemical, immunohisto chemical and lectin-binding reactions were almost identical to those in the genital lesion. However, although the axillary lesion was diagnosed as subclinical Paget's condition, the clinical course showed no aggressive or destructive nature. Our case suggests that not all subclinical Paget's conditions become malignant, and that in some cases the clear cells may be precursors of Paget's cells developing multifocally.     

Histological changes and involvement of apoptosis after photodynamic therapy for actinic keratoses

BACKGROUND: Photodynamic therapy (PDT), which employs a combination of a tumour-localizing photosensitizer and visible light, has been used to treat superficial malignancies in the epidermis. OBJECTIVES: To examine histological changes and the role of apoptosis in lesions of actinic keratosis (AK) after PDT using 5-aminolaevulinic acid (ALA) and excimer dye laser. METHODS: After topical ALA-PDT, biopsy specimens were collected from 18 skin lesions in 15 patients with AK. Paraffin-embedded sections of the skin specimens were stained with haematoxylin and eosin. The detection of apoptosis was performed using a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) method, antiactivated caspase-3 antibody and anti-Fas antibody. RESULTS: One hour after PDT, cells with eosinophilic cytoplasm and markedly stained nuclei were found, and vacuolation of some tumour cells was noted in the lower layer of the epidermis. An infiltrate of lymphocytes and neutrophils was observed in the upper layer of the dermis. One day after PDT, all layers of the epidermis exhibited slightly degenerative necrosis, with shadow cell formation and chromatin condensation around the nuclear membrane in the lower layer of the epidermis. Necrosis in all layers of the epidermis and lymphocyte infiltration in the dermis were found 3 days after PDT. Tumour cells had disappeared and regenerative thickening of the epidermis was observed 7 days after PDT. TUNEL staining revealed apoptosis-positive cells in the epidermis in 8 of 11 specimens obtained 1 day after PDT. Activated caspase-3 expression was noted in the lower layer of the epidermis in four of these eight TUNEL-positive specimens. CONCLUSIONS: Results suggested that apoptosis is involved in tumour cell death after PDT in patients with AK, and that it occurs within 1 day after PDT.     

ALA-PDT治疗囊肿性痤疮22例疗效观察

目的采用随机对照研究评价3%5-氨基酮戊酸光动力疗法(ALA-PDT)治疗囊肿性痤疮的疗效。方法治疗组22例接受1～3次ALA-PDT,对照组17例口服异维A酸胶丸20mg/d。皮损消退>90%或治疗持续6周为研究终点。结果治疗组第2,4,6周囊肿数目较对照组明显减少(P<0.01);治疗组第2,4,6周有效率分别为9.09%,40.91%,100%,而对照组分别为0,11.76%,58.82%,差异有统计学意义(P均<0.05);B超显示ALA-PDT治疗后囊肿较治疗前缩小或消失(P<0.01)。研究结束时,治疗组患者满意度较对照组高(P<0.05);治疗组复发率较对照组明显降低(P<0.05),且首次复发时间较对照组延长(P<0.05)。结论 ALA-PDT能够安全快速治愈囊肿性痤疮,同时延迟复发。