- Email: [email protected]
Extramammary Paget's disease treated with topical and systemic photodynamic therapy
Photodiagnosis and Photodynamic Therapy (2005) 2, 309—311
Extramammary Paget’s disease treated with topical and systemic photodynamic therapy V. Madan a, J. Loncaster b, D. Allan c, J. Lear a, L. Sheridan b, C. Leach b, E. Allan b,∗ a
Dermatology Centre, Hope Hospital, Salford, Manchester, UK Department of Clinical Oncology, Christie Hospital (NHS) Trust, Manchester, UK c North Western Medical Physics, Christie Hospital (NHS) Trust, Manchester, UK b
Available online 11 November 2005 KEYWORDS Extramammary Paget’s disease; Photodynamic therapy
Summary Surgical excision and radiotherapy for extramammary Paget’s disease (EMPD) at specific sites such as the groin and genitalia is often inappropriate. An 80-year-old man with histologically proven EMPD of the left groin and scrotum was referred for PDT. The lesion and normal skin thickness were measured by a 20 MHz, two-dimensional ‘B’ ultrasound scanner (US). ␦-5-Aminolaevulinic acid (ALA), was applied followed 6 h later by irradiation using a filtered xenon-arc lamp. Clinical improvement was apparent four weeks after first PDT session with a reduction in ulceration and lesion size and moderate thickness reduction on US. Superficial ulceration recurred 9 months after the fifth treatment. This recurrence was treated with intravenously administered porfimer sodium. This, followed by one topical PDT treatment resulted in significant clinical and US cure and the patient remains disease free at 1-year follow-up. © 2005 Elsevier B.V. All rights reserved.
Case report An 80-year-old man presented with 2-year history of progressive itchy lesion over the left groin and scrotum, unresponsive to topical antifungal treatment. Examination revealed a 10 cm × 10 cm erythematous ulcerated patch over the left groin extending to the scrotum (Fig. 1A). A skin biopsy from the lesion confirmed the diagnosis of extramammary Paget’s disease (EMPD). Initial ∗
Corresponding author. E-mail address: [email protected] (E. Allan).
investigations to find an underlying carcinoma including barium meal and enema were normal. Digital rectal examination of the prostate showed a T2 tumour. Transurethral resection of prostrate revealed Gleason 3 adenocarcinoma, which was treated with radical radiotherapy. Given the extent of EMPD, surgical treatment was considered inappropriate, and it was decided to treat the lesion with local photodynamic therapy (PDT). The lesion and normal skin thickness were measured by 20 MHz, sharp-focussed two-dimensional ‘B’ scanner with a measurement length of 12 mm (=224 side-by-side ‘A’ scans), depth of measure-
1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00100-6
310
V. Madan et al.
Figure 1 Paget’s disease of the groin and scrotum: (A) clinical picture at presentation; (B) improvement in erythema and ulceration post porfimer sodium treatment; (C) further reduction in erythema and ulceration; (D—F) comparative images from high frequency ultrasound (20 MHz, two-dimensional ‘B’ scanner). Section ‘a—b’ measures normal skin thickness. Hypoechogenic region ‘c—d’ represents area of active disease.
ment of 10 mm and resolution of 60 m × 130 m (Dermascan C ver. 3; Cortex Technology, Hadsund, Denmark). The parameter measured for normal skin adjacent to any lesion, was thickness of epidermis plus dermis, defined as the section ‘a—b’ in Fig. 1D. The maximum thickness of the EMPD was measured from the hypoechogenic region underlying the entry echo (‘c—d’ in Fig. 1D,E). The photosensitiser used was ␦-5-aminolaevulinic acid (ALA), applied topically as a 20% (wt:wt) emulsion in Unguentum Merck (Crawford Pharmaceuticals; Milton Keynes, UK). The cream was applied and left under an occlusive dressing for 6 h. The cream was then removed and a standard dose of 100 J cm−2 of red light (630 ± 15 nm) was given to the lesion plus 10% margin, by a filtered xenon-arc lamp. Power density varied inversely with the diameter of the lesion at each visit, between 47 and 84 mW cm−2 (20—35 min duration). Known likelihood of ALA PDT pain was controlled by locally infiltrating 0.5% bupivacaine immediately before the light exposure. On completion of treatment, hydrocortisone cream was applied for anti-inflammatory effect and a further occlusive dressing put on for 24 h as a precaution against photosensitisation by ambient light. After an initial inflammatory phase, which subsided in 3 days, clinical improvement was apparent after first PDT session with a reduction in ulceration
and size of the lesion. This corresponded with the moderate reduction in the thickness of the lesion on US (pre, 0.94 mm; post, −0.67). Further PDT treatments were carried out at varying intervals depending on the clinical signs (1—9 months). The lesion continued to improve with further PDT treatments, but superficial ulceration recurred 9 months after the fifth treatment. This recurrence was treated with systemic PDT with porfimer sodium administered intravenously at a dose of 1 mg kg−1 followed 48 h later by illumination with 630 nm red light from xenon-arc lamp. In view of the site and extent of the lesion, light was delivered at a reduced dose of 100 J cm−2 instead of the usual systemic PDT dose of 200 J cm−2 . Usual post-treatment light avoidance advice was given. This, followed by one topical PDT treatment for a local recurrence resulted in significant clinical and US improvement at a recent follow-up at 1 year (Fig. 1C).
Discussion Selective destruction of targeted abnormal cells has made PDT with topical ALA an effective tissue sparing and cosmetically acceptable treatment for premalignant and malignant skin lesions like Bowen’s disease and superficial BCC’s with cure
Extramammary Paget’s disease treated with topical and systemic photodynamic therapy rates in excess of 90% been routinely reported [1,2]. Standard surgical management of EMPD has a recurrence rate of 33—60% [3,4]. Even with Mohs micrographic surgery, a recurrence rate of 8—26% has been reported [5]. Radiotherapy has recently been shown to an effective alternative for treatment of EMPD in high-risk surgical candidates [6]. Radiotherapy is poorly tolerated and therefore unsuitable for certain sites like the groin. Porfimer Sodium (Photofrin® , Axcan Pharma Inc., Queb., Canada), which contains a purified mixture of oligomeric porphyrins, administered intravenously followed by illumination with 630 nm laser light is approved for the palliation of obstructing oesophageal cancer and small cell lung cancer, treatment of microinvasive non-small cell lung cancer and high-grade dysplasia in patients with Barrett’s oesophagus [7]. It has also been successfully used in the treatment of Mediterranean and HIVrelated Kaposi’s sarcoma and Bowen’s disease [8]. The use of 20 MHz US allows non-invasive measurement of thickness of skin lesions and is therefore helpful in monitoring response to treatment [9,10]. The skin thickness measured by US correlated with the clinical response in the present case thereby avoiding the need for serial skin biopsies, which in case of large EMPD may not represent areas of disease activity. ALA—PDT for the treatment of EMPD of the scrotum has been used in combination with Mohs micrographic surgery and wide local excision with excellent results [3]. A gradual reduction in the size of the lesion with ALA—PDT may make the lesion amenable to these surgical techniques, thereby minimising tissue destruction. It has also been used to reduce the recurrence of EMPD post surgery. Shieh et al. [11] treated 16 EMPD lesions with ALA—PDT, achieving 50% complete cure rate at 6 months. In addition, one patient with a partial response to ALA—PDT was treated with systemic Photofrin® achieving complete clinical and histological clearance at 1 year [11]. Local recurrence of EMPD with topical ALA—PDT can be explained by the highly selective destruction of the tumour cells targeted by the light source, sparing the peripheral abnormal cells of the clinically normal skin or due to the surviving Paget’s cells in the treated area. Other practical problems associated with the use of topical PDT which are
311
circumvented by systemic PDT are the difficulty in keeping the photosensitizer cream in place, difficulty in achieving a homogenous distribution of the sensitizer and the difficulty in achieving pain control during light therapy. As porfimer sodium causes more vascular destruction, healing time is prolonged and risk of scarring increased. It is also associated with 6—8 weeks of persistent photosensitivity and selflimiting post-treatment local inflammation. Thus, a combination of topical and systemic PDT with porfimer sodium to achieve initial control of the entire lesion followed by the use of topical PDT to local areas of recurrent disease may be an effective alternative to surgery in the management of bulky EMPD at otherwise difficult to treat anatomical sites in the elderly.
References [1] Morton CA, Whitehurst C, McColl JH, et al. Photodynamic therapy for large or multiple patches of Bowen disease and basal cell carcinoma. Arch Dermatol 2001;137(3):319—24. [2] Cairnduff F, Stringer MR, Hudson EJ, et al. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. Br J Cancer 1994;69(3):605—8. [3] Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget’s disease. Br J Dermatol 2000;142(1):59—65. [4] McCarter MD, Quan SH, Busam K. Long-term outcome of perianal Paget’s disease. Dis Colon Rectum 2003;46(5):612—6. [5] Hendi A, Brodland DG, Zitelli JA. Extramammary Paget’s disease: surgical treatment with Mohs micrographic surgery. J Am Acad Dermatol 2004;51(5):767—73. [6] Moreno-Arias GA, Conill C, Castells-Mas A. Radiotherapy for genital extramammary Paget’s disease in situ. Dermatol Surg 2001;27(6):587—90. [7] Axcan Pharma Inc. Website: http://www.axcan.com/ photofrin/productinfo.php?lang=1. Accessed on June 18, 2005. [8] Calzavara-Pinton PG, Szeimies RM, Ortel B. Photodynamic therapy with systemic administration of photosensitizers in dermatology. J Photochem Photobiol B 1996;36(2):225—31. [9] Fornage BD, McGavran MH, Duvic M. Imaging of the skin with 20 MHz US. Radiology 1993;189(1):69—76. [10] Allan E, Pye DA, Levine EL. Non-invasive pulsed ultrasound quantification of the resolution of basal cell carcinomas after photodynamic therapy. Lasers Med Sci 2002;17(4):230—7. [11] Shieh S, Dee AS, Cheney RT. Photodynamic therapy for the treatment of extramammary Paget’s disease. Br J Dermatol 2002;146(6):1000—5.
Extramammary Paget’s disease treated with topical and systemic photodynamic therapy V. Madan a, J. Loncaster b, D. Allan c, J. Lear a, L. Sheridan b, C. Leach b, E. Allan b,∗ a
Dermatology Centre, Hope Hospital, Salford, Manchester, UK Department of Clinical Oncology, Christie Hospital (NHS) Trust, Manchester, UK c North Western Medical Physics, Christie Hospital (NHS) Trust, Manchester, UK b
Available online 11 November 2005 KEYWORDS Extramammary Paget’s disease; Photodynamic therapy
Summary Surgical excision and radiotherapy for extramammary Paget’s disease (EMPD) at specific sites such as the groin and genitalia is often inappropriate. An 80-year-old man with histologically proven EMPD of the left groin and scrotum was referred for PDT. The lesion and normal skin thickness were measured by a 20 MHz, two-dimensional ‘B’ ultrasound scanner (US). ␦-5-Aminolaevulinic acid (ALA), was applied followed 6 h later by irradiation using a filtered xenon-arc lamp. Clinical improvement was apparent four weeks after first PDT session with a reduction in ulceration and lesion size and moderate thickness reduction on US. Superficial ulceration recurred 9 months after the fifth treatment. This recurrence was treated with intravenously administered porfimer sodium. This, followed by one topical PDT treatment resulted in significant clinical and US cure and the patient remains disease free at 1-year follow-up. © 2005 Elsevier B.V. All rights reserved.
Case report An 80-year-old man presented with 2-year history of progressive itchy lesion over the left groin and scrotum, unresponsive to topical antifungal treatment. Examination revealed a 10 cm × 10 cm erythematous ulcerated patch over the left groin extending to the scrotum (Fig. 1A). A skin biopsy from the lesion confirmed the diagnosis of extramammary Paget’s disease (EMPD). Initial ∗
Corresponding author. E-mail address: [email protected] (E. Allan).
investigations to find an underlying carcinoma including barium meal and enema were normal. Digital rectal examination of the prostate showed a T2 tumour. Transurethral resection of prostrate revealed Gleason 3 adenocarcinoma, which was treated with radical radiotherapy. Given the extent of EMPD, surgical treatment was considered inappropriate, and it was decided to treat the lesion with local photodynamic therapy (PDT). The lesion and normal skin thickness were measured by 20 MHz, sharp-focussed two-dimensional ‘B’ scanner with a measurement length of 12 mm (=224 side-by-side ‘A’ scans), depth of measure-
1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00100-6
310
V. Madan et al.
Figure 1 Paget’s disease of the groin and scrotum: (A) clinical picture at presentation; (B) improvement in erythema and ulceration post porfimer sodium treatment; (C) further reduction in erythema and ulceration; (D—F) comparative images from high frequency ultrasound (20 MHz, two-dimensional ‘B’ scanner). Section ‘a—b’ measures normal skin thickness. Hypoechogenic region ‘c—d’ represents area of active disease.
ment of 10 mm and resolution of 60 m × 130 m (Dermascan C ver. 3; Cortex Technology, Hadsund, Denmark). The parameter measured for normal skin adjacent to any lesion, was thickness of epidermis plus dermis, defined as the section ‘a—b’ in Fig. 1D. The maximum thickness of the EMPD was measured from the hypoechogenic region underlying the entry echo (‘c—d’ in Fig. 1D,E). The photosensitiser used was ␦-5-aminolaevulinic acid (ALA), applied topically as a 20% (wt:wt) emulsion in Unguentum Merck (Crawford Pharmaceuticals; Milton Keynes, UK). The cream was applied and left under an occlusive dressing for 6 h. The cream was then removed and a standard dose of 100 J cm−2 of red light (630 ± 15 nm) was given to the lesion plus 10% margin, by a filtered xenon-arc lamp. Power density varied inversely with the diameter of the lesion at each visit, between 47 and 84 mW cm−2 (20—35 min duration). Known likelihood of ALA PDT pain was controlled by locally infiltrating 0.5% bupivacaine immediately before the light exposure. On completion of treatment, hydrocortisone cream was applied for anti-inflammatory effect and a further occlusive dressing put on for 24 h as a precaution against photosensitisation by ambient light. After an initial inflammatory phase, which subsided in 3 days, clinical improvement was apparent after first PDT session with a reduction in ulceration
and size of the lesion. This corresponded with the moderate reduction in the thickness of the lesion on US (pre, 0.94 mm; post, −0.67). Further PDT treatments were carried out at varying intervals depending on the clinical signs (1—9 months). The lesion continued to improve with further PDT treatments, but superficial ulceration recurred 9 months after the fifth treatment. This recurrence was treated with systemic PDT with porfimer sodium administered intravenously at a dose of 1 mg kg−1 followed 48 h later by illumination with 630 nm red light from xenon-arc lamp. In view of the site and extent of the lesion, light was delivered at a reduced dose of 100 J cm−2 instead of the usual systemic PDT dose of 200 J cm−2 . Usual post-treatment light avoidance advice was given. This, followed by one topical PDT treatment for a local recurrence resulted in significant clinical and US improvement at a recent follow-up at 1 year (Fig. 1C).
Discussion Selective destruction of targeted abnormal cells has made PDT with topical ALA an effective tissue sparing and cosmetically acceptable treatment for premalignant and malignant skin lesions like Bowen’s disease and superficial BCC’s with cure
Extramammary Paget’s disease treated with topical and systemic photodynamic therapy rates in excess of 90% been routinely reported [1,2]. Standard surgical management of EMPD has a recurrence rate of 33—60% [3,4]. Even with Mohs micrographic surgery, a recurrence rate of 8—26% has been reported [5]. Radiotherapy has recently been shown to an effective alternative for treatment of EMPD in high-risk surgical candidates [6]. Radiotherapy is poorly tolerated and therefore unsuitable for certain sites like the groin. Porfimer Sodium (Photofrin® , Axcan Pharma Inc., Queb., Canada), which contains a purified mixture of oligomeric porphyrins, administered intravenously followed by illumination with 630 nm laser light is approved for the palliation of obstructing oesophageal cancer and small cell lung cancer, treatment of microinvasive non-small cell lung cancer and high-grade dysplasia in patients with Barrett’s oesophagus [7]. It has also been successfully used in the treatment of Mediterranean and HIVrelated Kaposi’s sarcoma and Bowen’s disease [8]. The use of 20 MHz US allows non-invasive measurement of thickness of skin lesions and is therefore helpful in monitoring response to treatment [9,10]. The skin thickness measured by US correlated with the clinical response in the present case thereby avoiding the need for serial skin biopsies, which in case of large EMPD may not represent areas of disease activity. ALA—PDT for the treatment of EMPD of the scrotum has been used in combination with Mohs micrographic surgery and wide local excision with excellent results [3]. A gradual reduction in the size of the lesion with ALA—PDT may make the lesion amenable to these surgical techniques, thereby minimising tissue destruction. It has also been used to reduce the recurrence of EMPD post surgery. Shieh et al. [11] treated 16 EMPD lesions with ALA—PDT, achieving 50% complete cure rate at 6 months. In addition, one patient with a partial response to ALA—PDT was treated with systemic Photofrin® achieving complete clinical and histological clearance at 1 year [11]. Local recurrence of EMPD with topical ALA—PDT can be explained by the highly selective destruction of the tumour cells targeted by the light source, sparing the peripheral abnormal cells of the clinically normal skin or due to the surviving Paget’s cells in the treated area. Other practical problems associated with the use of topical PDT which are
311
circumvented by systemic PDT are the difficulty in keeping the photosensitizer cream in place, difficulty in achieving a homogenous distribution of the sensitizer and the difficulty in achieving pain control during light therapy. As porfimer sodium causes more vascular destruction, healing time is prolonged and risk of scarring increased. It is also associated with 6—8 weeks of persistent photosensitivity and selflimiting post-treatment local inflammation. Thus, a combination of topical and systemic PDT with porfimer sodium to achieve initial control of the entire lesion followed by the use of topical PDT to local areas of recurrent disease may be an effective alternative to surgery in the management of bulky EMPD at otherwise difficult to treat anatomical sites in the elderly.
References [1] Morton CA, Whitehurst C, McColl JH, et al. Photodynamic therapy for large or multiple patches of Bowen disease and basal cell carcinoma. Arch Dermatol 2001;137(3):319—24. [2] Cairnduff F, Stringer MR, Hudson EJ, et al. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. Br J Cancer 1994;69(3):605—8. [3] Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget’s disease. Br J Dermatol 2000;142(1):59—65. [4] McCarter MD, Quan SH, Busam K. Long-term outcome of perianal Paget’s disease. Dis Colon Rectum 2003;46(5):612—6. [5] Hendi A, Brodland DG, Zitelli JA. Extramammary Paget’s disease: surgical treatment with Mohs micrographic surgery. J Am Acad Dermatol 2004;51(5):767—73. [6] Moreno-Arias GA, Conill C, Castells-Mas A. Radiotherapy for genital extramammary Paget’s disease in situ. Dermatol Surg 2001;27(6):587—90. [7] Axcan Pharma Inc. Website: http://www.axcan.com/ photofrin/productinfo.php?lang=1. Accessed on June 18, 2005. [8] Calzavara-Pinton PG, Szeimies RM, Ortel B. Photodynamic therapy with systemic administration of photosensitizers in dermatology. J Photochem Photobiol B 1996;36(2):225—31. [9] Fornage BD, McGavran MH, Duvic M. Imaging of the skin with 20 MHz US. Radiology 1993;189(1):69—76. [10] Allan E, Pye DA, Levine EL. Non-invasive pulsed ultrasound quantification of the resolution of basal cell carcinomas after photodynamic therapy. Lasers Med Sci 2002;17(4):230—7. [11] Shieh S, Dee AS, Cheney RT. Photodynamic therapy for the treatment of extramammary Paget’s disease. Br J Dermatol 2002;146(6):1000—5.