CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Radiation-induced morphoea treated with UVA-1 phototherapy D. Lim,1 S. Johnston,2 L. Novakovic3 and L. Fearfield1,4 1
Department of Dermatology, Chelsea and Westminster Hospital, London, UK; 2Department of Breast Oncology, Royal Marsden Hospital, London, UK; Department of Photodermatology, St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK; and 4Department of Dermatology, Royal Marsden Hospital, London, UK 3
doi:10.1111/ced.12345
Summary
Morphoea is a localized inflammatory disorder of the dermis and subcutaneous fat and radiotherapy is a rarely reported cause (estimated incidence of 2 per 1000). Morphoea is commonly mistaken for an inflammatory recurrence of breast cancer, resulting in unnecessary investigations and treatment. We report the case of a 40year-old woman who developed radiation-induced morphoea of the breast 7 months following adjuvant radiotherapy. She was treated with topical and systemic steroids as well as psoralen plus ultraviolet (UV)A before proceeding to UVA1 phototherapy. We also review the literature and discuss other management options.
Radiation-induced morphoea (RIM) is a rarely reported cause of morphoea and is commonly mistaken for an inflammatory recurrence of breast cancer. It is underrecognized by oncologists and this can lead to unnecessary investigations and treatment. Unfortunately, there is no consensus for treatment, in large part because of the rarity of the disorder and a resulting lack of studies. Treatment success is variable and it can lead to cosmetically poor outcomes that can have a devastating effect on young women. Unfortunately, with large defects on a background of irradiated skin, surgical reconstruction is not an easy option to pursue.
Report A 40-year-old, previously well woman was diagnosed with a localized (stage 1A) grade 2 left-sided breast cancer, which was positive for oestrogen receptor (8+), progesterone receptor (8+) and HER2 (human epidermal growth factor receptor 2) (3+). She subsequently underwent neoadjuvant chemotherapy (four cycles of epirubicin–cyclophosphamide and four cycles of docetaxel) Correspondence: Dr David Lim, Department of Dermatology, Chelsea and Westminster Hospital, Fulham Road, London, SW10 9NH, UK E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 31 January 2014
612
Clinical and Experimental Dermatology (2014) 39, pp612–615
followed by a breast-conserving wide local excision. Adjuvant treatment included radiotherapy (40 Gy) over 15 fractions and 13.35 Gy over 5 fractions to the tumour bed, along with 17 cycles of trastuzumab and tamoxifen (20 mg daily). The patient did not develop any localized skin reactions during or immediately after radiotherapy. Seven months after radiotherapy was completed, the skin over the patient’s left breast became progressively red and painful and she was referred to a breast oncologist. The initial concern was for an early inflammatory recurrence of breast cancer, given the clinical appearance and risk factors, including the HER2 status. Investigations for recurrent breast cancer were carried out, including baseline investigations for further chemotherapy. Two subsequent biopsies failed to demonstrate evidence of breast cancer. The affected area progressively increased and the pain accelerated over the following 6 weeks, so the patient was referred to a dermatologist for review. On physical examination, a rectangular, sharply demarcated, red and indurated waxy plaque was seen on the left breast. The affected area correlated with her previous radiotherapy treatment field (Fig. 1b). A clinical diagnosis of morphoea was made and histological review demonstrated accumulation and hyalinization of collagen, associated with a focal deep perivascular lymphoplasmacytic infiltrate (Fig. 2). These findings were consistent with early RIM. Autoimmune profiling and Borrelia species serology testing
ª 2014 British Association of Dermatologists
RIM treated with UVA-1 D. Lim et al.
were negative. The patient’s personal and family histories were negative for autoimmune diseases. Magnetic resonance imaging (of the left breast and chest wall confirmed inflammation confined to the skin of the left breast (Fig. 3). The underlying tissues were unaffected.
The patient was initially treated with topical steroids, which failed to halt the progression of the RIM and she was commenced on oral prednisolone 30 mg daily. She noticed a dramatic improvement in pain within 2 days of starting prednisolone, and after
(a)
(b)
(c)
(d)
Figure 1 Progression of skin changes
through the development of morphoea and treatment. (a) Skin following excision of breast carcinoma. (b) At presentation there was a rectangular, sharply demarcated area of red and tight skin that correlated with the previous radiotherapy treatment field (tattoos visible). (c) After cessation of topical and systemic steroids, the acute erythema had been replaced with tight sclerosis and loss of underlying breast tissue volume. (d) After cessation of ultraviolet A1 treatment, there was softening and reduction of the involved area.
(a)
(b)
(c)
Figure 2 (a–c) Accumulation of abnormal collagen and a focal perivascular infiltrate. Haematoxylin and eosin, original magnification (a) 9 10; (b) 9 40; (c) 9 40.
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp612–615
613
RIM treated with UVA-1 D. Lim et al.
Figure 3 Post gadolinium T1 fat-saturated magnetic resonance
imaging showed inflammation confined to the skin of the left breast.
1 week, the skin had softened markedly. Prednisolone was gradually tapered over 2 weeks, resulting in a recurrence of symptoms. A more gradual taper was successfully continued over the subsequent 4 weeks. Twice-weekly topical (gel) psoralen plus ultraviolet A (PUVA) was commenced, leading to mild improvement. Unfortunately, after 22 treatments (107.8 J/cm2), the improvement reached a plateau and was referred for treatment with UVA1 phototherapy. Overall, the patient had 47 treatments of UVA1, with a cumulative dose of 2633.60 mJ/cm2. This was started at medium dose (35 treatments at 50 J/cm2) and progressed to high dose (12 treatments at 80 J/cm2). The UVA1 treatment was moderately successful as the area softened and was more comfortable, with less pain experienced by the patient. The patient stated that she had more improvement with the high-dose UVA1 compared with the medium-dose treatment. Unfortunately, she still has occasional pain. She also lost a considerable volume of underlying breast tissue (Fig. 1c). Methotrexate has not been used because of concerns about encouraging a recurrence of the breast cancer. Surgical excision of the abnormal skin was also considered; however, this would require creating a large surgical defect and subsequent repair within a previous radiotherapy treatment field carries a substantial risk of wound failure. Morphoea is an uncommon inflammatory disorder of the dermis and subcutaneous fat that progresses to fibrosis. Radiation is a rarely reported cause of morphoea, with an estimated incidence of 2 per 1000. This compares with an all-cause morphoea incidence of 2.7 per 100 000 in the general population. Most cases of RIM occur between 1 and 12 months after
614
Clinical and Experimental Dermatology (2014) 39, pp612–615
radiation, but it has been reported to occur as late as 32 years post-radiation. The pathophysiology of RIM is unknown, but several theories have been postulated. Davis et al.1 suggested that radiation induces neoantigen formation, which subsequently stimulates secretion of transforming growth factor (TGF)-b, which in turn strongly induces fibroblast activation, collagen synthesis and, hence, excessive fibrosis. Reddy et al.2 discussed radiation having a direct effect on fibroblasts, resulting in differentiation of the fibroblasts to a more active form and thus leading to excess collagen formation. RIM normally presents with a gradual onset of an area of hardened, red, uncomfortable skin, which correlates with a previous radiotherapy treatment field. However, there have been reports of involvement outside the irradiated field.3 RIM is commonly mistaken for an inflammatory recurrence of breast cancer, classically Paget disease of the breast. However, RIM can usually be distinguished by its rectangular shape and sharp demarcation. Although RIM is normally diagnosed clinically, a low threshold for biopsy should be maintained. Histological findings are similar to those of all-cause morphoea and depend on the stage of disease at which the biopsy is taken. Early findings show dermal oedema with degeneration of collagen and there is sometimes a sparse lymphocytic infiltrate with associated plasma cells and macrophages. Late findings are consistent with fibrosis, with dense collagen causing a thickening of the dermis and loss of appendages. Radiation changes may be evident in the surrounding tissues. Treatment recommendations for RIM are limited to individual case reports and small case series and most of these have used treatments for all-cause morphoea. The most compelling studies for all-cause morphoea have looked at the combination of prednisolone and methotrexate or at various forms of UVA1 phototherapy. Both the combination of methotrexate and methylprednisolone or the use of highdose UVA1 (30 treatments at 130 J/cm2) can halt disease progression in > 90% of patients.4,5 It appears that lower-dose regimens of UVA1 are less effective but still beneficial.6,7 UVA and UVB also appear to be effective.8 Early imaging is helpful to determine the extent and depth of morphoea. We have also found serial photography invaluable and would recommend this be performed at least once per month to establish progress and response to treatment. However, our patient’s images have demonstrated a dramatic shrinkage of the
ª 2014 British Association of Dermatologists
RIM treated with UVA-1 D. Lim et al.
breast tissue volume, which is having an ongoing impact on her self-image and confidence. In an attempt to halt the early inflammatory phase and preserve underlying breast tissue, particularly in young women, we recommend early aggressive treatment with high-dose oral prednisolone or pulse intravenous methylprednisolone. Unfortunately, the delayed presentation and diagnosis has probably limited the efficacy of treatment in our patient.
Learning points A rectangular, sharply demarcated eruption
suggests exposure to a mechanical device. Specialist input should be sought when there is
diagnostic uncertainty RIM can have varied histological findings that
depend on stage at presentation. There is no clear consensus for treatment of
radiation-induced morphoea, but systemic steroids and UVA1 appear the most promising therapies.
2 Reddy S, Pui J, Gold L, Mitnick H. Postirradiation morphea and subcutaneous polyarteritis nodosa: case report and literature review. Semin Arthritis Rheum 2005; 34: 728–34. 3 Arden-Jones M, Black M. Widespread morphoea following radiotherapy for carcinoma of the breast. Clin Exp Dermatol 2003; 28: 160–2. 4 Weibel L, Sampaio M, Visentin M et al. Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children. Br J Dermatol 2006; 155: 1013–20. 5 Stege H, Bemeburg M, Humke S et al. High-dose UVA1 scleroderma radiation therapy for localized. J Am Acad Dermatol 1997; 36: 938–44. 6 Kerscher M, Volkenandt M, Gruss C et al. Low-dose UVA1 phototherapy for treatment of localized scleroderma. J Am Acad Dermatol 1998; 38: 21–6. 7 Sator P, Radakovic S, Schulmeister K et al. Medium-dose is more effective than low-dose ultraviolet al phototherapy for localized scleroderma as shown by 20-MHz ultrasound assessment. J Am Acad Dermatol 2008; 60: 786–90. 8 Kroft E, Berkhof N, van de Kerkhof P et al. Ultraviolet A phototherapy for sclerotic skin diseases: a systematic review. J Am Acad Dermatol 2008; 59: 1017–30.
References 1 Davis D, Cohen P, McNeese M, Duvic M. Localized scleroderma in breast cancer patients treated with supervoltage external beam radiation: radiation port scleroderma. J Am Acad Dermatol 1996; 35: 923–7.
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp612–615
615
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Radiation-induced morphoea treated with UVA-1 phototherapy D. Lim,1 S. Johnston,2 L. Novakovic3 and L. Fearfield1,4 1
Department of Dermatology, Chelsea and Westminster Hospital, London, UK; 2Department of Breast Oncology, Royal Marsden Hospital, London, UK; Department of Photodermatology, St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK; and 4Department of Dermatology, Royal Marsden Hospital, London, UK 3
doi:10.1111/ced.12345
Summary
Morphoea is a localized inflammatory disorder of the dermis and subcutaneous fat and radiotherapy is a rarely reported cause (estimated incidence of 2 per 1000). Morphoea is commonly mistaken for an inflammatory recurrence of breast cancer, resulting in unnecessary investigations and treatment. We report the case of a 40year-old woman who developed radiation-induced morphoea of the breast 7 months following adjuvant radiotherapy. She was treated with topical and systemic steroids as well as psoralen plus ultraviolet (UV)A before proceeding to UVA1 phototherapy. We also review the literature and discuss other management options.
Radiation-induced morphoea (RIM) is a rarely reported cause of morphoea and is commonly mistaken for an inflammatory recurrence of breast cancer. It is underrecognized by oncologists and this can lead to unnecessary investigations and treatment. Unfortunately, there is no consensus for treatment, in large part because of the rarity of the disorder and a resulting lack of studies. Treatment success is variable and it can lead to cosmetically poor outcomes that can have a devastating effect on young women. Unfortunately, with large defects on a background of irradiated skin, surgical reconstruction is not an easy option to pursue.
Report A 40-year-old, previously well woman was diagnosed with a localized (stage 1A) grade 2 left-sided breast cancer, which was positive for oestrogen receptor (8+), progesterone receptor (8+) and HER2 (human epidermal growth factor receptor 2) (3+). She subsequently underwent neoadjuvant chemotherapy (four cycles of epirubicin–cyclophosphamide and four cycles of docetaxel) Correspondence: Dr David Lim, Department of Dermatology, Chelsea and Westminster Hospital, Fulham Road, London, SW10 9NH, UK E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 31 January 2014
612
Clinical and Experimental Dermatology (2014) 39, pp612–615
followed by a breast-conserving wide local excision. Adjuvant treatment included radiotherapy (40 Gy) over 15 fractions and 13.35 Gy over 5 fractions to the tumour bed, along with 17 cycles of trastuzumab and tamoxifen (20 mg daily). The patient did not develop any localized skin reactions during or immediately after radiotherapy. Seven months after radiotherapy was completed, the skin over the patient’s left breast became progressively red and painful and she was referred to a breast oncologist. The initial concern was for an early inflammatory recurrence of breast cancer, given the clinical appearance and risk factors, including the HER2 status. Investigations for recurrent breast cancer were carried out, including baseline investigations for further chemotherapy. Two subsequent biopsies failed to demonstrate evidence of breast cancer. The affected area progressively increased and the pain accelerated over the following 6 weeks, so the patient was referred to a dermatologist for review. On physical examination, a rectangular, sharply demarcated, red and indurated waxy plaque was seen on the left breast. The affected area correlated with her previous radiotherapy treatment field (Fig. 1b). A clinical diagnosis of morphoea was made and histological review demonstrated accumulation and hyalinization of collagen, associated with a focal deep perivascular lymphoplasmacytic infiltrate (Fig. 2). These findings were consistent with early RIM. Autoimmune profiling and Borrelia species serology testing
ª 2014 British Association of Dermatologists
RIM treated with UVA-1 D. Lim et al.
were negative. The patient’s personal and family histories were negative for autoimmune diseases. Magnetic resonance imaging (of the left breast and chest wall confirmed inflammation confined to the skin of the left breast (Fig. 3). The underlying tissues were unaffected.
The patient was initially treated with topical steroids, which failed to halt the progression of the RIM and she was commenced on oral prednisolone 30 mg daily. She noticed a dramatic improvement in pain within 2 days of starting prednisolone, and after
(a)
(b)
(c)
(d)
Figure 1 Progression of skin changes
through the development of morphoea and treatment. (a) Skin following excision of breast carcinoma. (b) At presentation there was a rectangular, sharply demarcated area of red and tight skin that correlated with the previous radiotherapy treatment field (tattoos visible). (c) After cessation of topical and systemic steroids, the acute erythema had been replaced with tight sclerosis and loss of underlying breast tissue volume. (d) After cessation of ultraviolet A1 treatment, there was softening and reduction of the involved area.
(a)
(b)
(c)
Figure 2 (a–c) Accumulation of abnormal collagen and a focal perivascular infiltrate. Haematoxylin and eosin, original magnification (a) 9 10; (b) 9 40; (c) 9 40.
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp612–615
613
RIM treated with UVA-1 D. Lim et al.
Figure 3 Post gadolinium T1 fat-saturated magnetic resonance
imaging showed inflammation confined to the skin of the left breast.
1 week, the skin had softened markedly. Prednisolone was gradually tapered over 2 weeks, resulting in a recurrence of symptoms. A more gradual taper was successfully continued over the subsequent 4 weeks. Twice-weekly topical (gel) psoralen plus ultraviolet A (PUVA) was commenced, leading to mild improvement. Unfortunately, after 22 treatments (107.8 J/cm2), the improvement reached a plateau and was referred for treatment with UVA1 phototherapy. Overall, the patient had 47 treatments of UVA1, with a cumulative dose of 2633.60 mJ/cm2. This was started at medium dose (35 treatments at 50 J/cm2) and progressed to high dose (12 treatments at 80 J/cm2). The UVA1 treatment was moderately successful as the area softened and was more comfortable, with less pain experienced by the patient. The patient stated that she had more improvement with the high-dose UVA1 compared with the medium-dose treatment. Unfortunately, she still has occasional pain. She also lost a considerable volume of underlying breast tissue (Fig. 1c). Methotrexate has not been used because of concerns about encouraging a recurrence of the breast cancer. Surgical excision of the abnormal skin was also considered; however, this would require creating a large surgical defect and subsequent repair within a previous radiotherapy treatment field carries a substantial risk of wound failure. Morphoea is an uncommon inflammatory disorder of the dermis and subcutaneous fat that progresses to fibrosis. Radiation is a rarely reported cause of morphoea, with an estimated incidence of 2 per 1000. This compares with an all-cause morphoea incidence of 2.7 per 100 000 in the general population. Most cases of RIM occur between 1 and 12 months after
614
Clinical and Experimental Dermatology (2014) 39, pp612–615
radiation, but it has been reported to occur as late as 32 years post-radiation. The pathophysiology of RIM is unknown, but several theories have been postulated. Davis et al.1 suggested that radiation induces neoantigen formation, which subsequently stimulates secretion of transforming growth factor (TGF)-b, which in turn strongly induces fibroblast activation, collagen synthesis and, hence, excessive fibrosis. Reddy et al.2 discussed radiation having a direct effect on fibroblasts, resulting in differentiation of the fibroblasts to a more active form and thus leading to excess collagen formation. RIM normally presents with a gradual onset of an area of hardened, red, uncomfortable skin, which correlates with a previous radiotherapy treatment field. However, there have been reports of involvement outside the irradiated field.3 RIM is commonly mistaken for an inflammatory recurrence of breast cancer, classically Paget disease of the breast. However, RIM can usually be distinguished by its rectangular shape and sharp demarcation. Although RIM is normally diagnosed clinically, a low threshold for biopsy should be maintained. Histological findings are similar to those of all-cause morphoea and depend on the stage of disease at which the biopsy is taken. Early findings show dermal oedema with degeneration of collagen and there is sometimes a sparse lymphocytic infiltrate with associated plasma cells and macrophages. Late findings are consistent with fibrosis, with dense collagen causing a thickening of the dermis and loss of appendages. Radiation changes may be evident in the surrounding tissues. Treatment recommendations for RIM are limited to individual case reports and small case series and most of these have used treatments for all-cause morphoea. The most compelling studies for all-cause morphoea have looked at the combination of prednisolone and methotrexate or at various forms of UVA1 phototherapy. Both the combination of methotrexate and methylprednisolone or the use of highdose UVA1 (30 treatments at 130 J/cm2) can halt disease progression in > 90% of patients.4,5 It appears that lower-dose regimens of UVA1 are less effective but still beneficial.6,7 UVA and UVB also appear to be effective.8 Early imaging is helpful to determine the extent and depth of morphoea. We have also found serial photography invaluable and would recommend this be performed at least once per month to establish progress and response to treatment. However, our patient’s images have demonstrated a dramatic shrinkage of the
ª 2014 British Association of Dermatologists
RIM treated with UVA-1 D. Lim et al.
breast tissue volume, which is having an ongoing impact on her self-image and confidence. In an attempt to halt the early inflammatory phase and preserve underlying breast tissue, particularly in young women, we recommend early aggressive treatment with high-dose oral prednisolone or pulse intravenous methylprednisolone. Unfortunately, the delayed presentation and diagnosis has probably limited the efficacy of treatment in our patient.
Learning points A rectangular, sharply demarcated eruption
suggests exposure to a mechanical device. Specialist input should be sought when there is
diagnostic uncertainty RIM can have varied histological findings that
depend on stage at presentation. There is no clear consensus for treatment of
radiation-induced morphoea, but systemic steroids and UVA1 appear the most promising therapies.
2 Reddy S, Pui J, Gold L, Mitnick H. Postirradiation morphea and subcutaneous polyarteritis nodosa: case report and literature review. Semin Arthritis Rheum 2005; 34: 728–34. 3 Arden-Jones M, Black M. Widespread morphoea following radiotherapy for carcinoma of the breast. Clin Exp Dermatol 2003; 28: 160–2. 4 Weibel L, Sampaio M, Visentin M et al. Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children. Br J Dermatol 2006; 155: 1013–20. 5 Stege H, Bemeburg M, Humke S et al. High-dose UVA1 scleroderma radiation therapy for localized. J Am Acad Dermatol 1997; 36: 938–44. 6 Kerscher M, Volkenandt M, Gruss C et al. Low-dose UVA1 phototherapy for treatment of localized scleroderma. J Am Acad Dermatol 1998; 38: 21–6. 7 Sator P, Radakovic S, Schulmeister K et al. Medium-dose is more effective than low-dose ultraviolet al phototherapy for localized scleroderma as shown by 20-MHz ultrasound assessment. J Am Acad Dermatol 2008; 60: 786–90. 8 Kroft E, Berkhof N, van de Kerkhof P et al. Ultraviolet A phototherapy for sclerotic skin diseases: a systematic review. J Am Acad Dermatol 2008; 59: 1017–30.
References 1 Davis D, Cohen P, McNeese M, Duvic M. Localized scleroderma in breast cancer patients treated with supervoltage external beam radiation: radiation port scleroderma. J Am Acad Dermatol 1996; 35: 923–7.
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp612–615
615
