660 Correspondence
the eponym ‘Nakajo–Nishimura syndrome’ as the unifying nomenclature of these three syndromes. However, avoidance of eponyms has become the public tendency in recent years and an acronym is preferred which summarizes information of the disease. Nevertheless, the acronyms JMP and CANDLE seem to represent only limited aspects of this disease, the advanced phenotypes and the pathological features, respectively. Indeed, Online Mendelian Inheritance in Man (OMIM) #256040, in which the designation ‘Nakajo syndrome’ has long been registered until recently, now includes all three syndromes under the new designation ‘autoinflammation, lipodystrophy and dermatosis (ALDD) syndrome’. Furthermore, a new conceptual acronym ‘proteasome-associated autoinflammatory syndromes (PRAAS)’ has recently been proposed as the umbrella term for these three syndromes.10 However, to apply this designation, proteasome dysfunction due to the novel mutation should be evident. Collectively, we believe that it would be both appropriate and desirable to discuss the distinction of these syndromes from the genetic and clinical aspects and, if they are really included in the same entity, to select the most suitable designation for the definition. 1
Department of Dermatology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan 2 Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayamashi, Tokyo 189-0002, Japan 3 Department of Pediatrics and Child Health, Nihon University School of Medicine, Nihon University Itabashi Hospital, 30-1, Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan Correspondence: Nobuo Kanazawa. E-mail: [email protected]
N. KANAZAWA1 K. KUNIMOTO1 N. ISHII2 Y. INAMO3 F. FURUKAWA1
References 1 Kluk J, Rustin M, Brogan PA et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a report of a novel mutation and review of the literature. Br J Dermatol 2014; 170:215–17. 2 Torrelo A, Patel S, Colmenero I et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol 2010; 62:489–95. 3 Kunimoto K, Kimura A, Uede K et al. A new infant case of NakajoNishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. Dermatology 2013; 227:26–30. 4 Garg A, Hernandez MD, Sousa AB et al. An autosomal recessive syndrome of joint contracture, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J Clin Endcrinol Metab 2010; 95:E48–63. 5 Agarwal AK, Xing C, DeMartino GN et al. PSMB8 encoding the b5i proteasome subunit is mutated in joint contractures, muscle
British Journal of Dermatology (2014) 171, pp657–678
6
7
8
9
10
atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 2010; 87:866–72. Kitano Y, Matsunaga E, Morimoto T et al. A syndrome with nodular erythema, elongated and thickened fingers, and emaciation. Arch Dermatol 1985; 121:1053–6. Arima K, Kinoshita A, Mishima H et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci USA 2011; 108:14914–19. Liu Y, Ramot Y, Torrelo A et al. Mutations in PSMB8 cause CANDLE syndrome with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 2012; 64:895–907. Messia V, Pardeo M, Nicolai R et al. P02-16 – a novel PSMB8 mutation causing candle syndrome. Pediatr Rheumatol 2013; 11(Suppl. 1):A123. McDermott A, Jesus AA, Liu Y et al. A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations. J Am Acad Dermatol 2013; 69:e29–32.
Funding sources: This work was supported by a grant from the Japan Society for Promotion of Science (N.K. and K.K.) and Japan Ministry of Health, Labor and Welfare. Conflicts of interest: none declared.
Primary cutaneous Ewing sarcoma following metastasis to the bone and lymph nodes DOI: 10.1111/bjd.12979 DEAR EDITOR, Ewing sarcoma (ES) is a rare malignant round-cell tumour that primarily affects the skeletal system and is commonly diagnosed in children and young adults. It was first described in 1921.1 ES tumours consist of small, round cells that mostly express CD99, and that are characterized by a specific chromosomal translocation involving the EWSR1 gene on chromosome 22, with an erythroblastosis virus-transforming gene (in most cases, the FLI1 gene), thus resulting in a fusion oncogene.2 A 9-year-old Japanese girl found a subcutaneous tumour measuring 15 9 20 cm on the left side of her upper back 1 month prior to admission. She visited a dermatological clinic because the lesion increased slightly in size. At the clinic, the tumour was found to be enucleated, and the histological findings suggested a possible diagnosis of ES. Therefore, the patient was admitted to our hospital for further examination and treatment. Physical examination showed only a surgical scar on the left side of the patient’s upper back. No regional lymph node involvement was detectable. The findings of a blood test were within normal limits. Histological examination revealed a tumour, composed of round cells exhibiting dysplastic changes, within the dermis (Fig. 1a). Mitotic cells were also observed (Fig. 1b). Microscopic vascular invasion of tumour cells was not observed. Immunohistochemical study showed that most of the tumour cells expressed CD99 (Fig. 1c) and vimentin (Fig. 1d). Fluorescence in situ hybridization analysis using an © 2014 British Association of Dermatologists
Correspondence 661
EWSR1 break-apart probe detected translocation of EWSR1 (Fig. 1e). Furthermore, reverse-transcriptase polymerase chain reaction analysis and direct sequencing identified EWSR1 gene fusion (the fusion of EWSR1 exon 7 to FLI1 exon 6) (Fig. 1f). Positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) of the whole body did not detect any abnormalities in the lymph nodes or internal organs. No bone marrow involvement was observed. Based on these findings, the patient was diagnosed with primary cutaneous ES. An extensive excision was performed with a 5-cm surgical margin from the surgical scar, and the patient received two cycles of chemotherapy, including cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide and etoposide. However, 8 months after the administration of chemotherapy, PET/CT and enhanced MRI detected multiple lesions in the bilateral cervical lymph nodes, left ilium and right femur, suggesting multiple metastases (Fig. 2a–c). Although tissue specimens obtained from the left ilium showed only a few abnormal cells and did not exhibit findings suggestive of metastases of ES, eight additional cycles of chemotherapy were administered. Most of the lesions in the lymph nodes and bone reduced in size, although they did not disappear completely. Therefore, an autologous peripheral blood stem cell transplantation was performed following the administration of high-dose chemotherapy, which included melphalan, etoposide and carboplatin. The
Fig 1. (a) Histological examination revealed a tumour within the dermis (haematoxylin and eosin stain). (b) The tumour was composed of basaloid round cells with severe dysplasia (haematoxylin and eosin stain, original magnification 200 9). The expression of (c) CD99 and (d) vimentin was observed in the infiltrated tumour cells (original magnification 200 9). (e) Fluorescence in situ hybridization/EWSR1 with break-apart positive for the translocation of EWSR1. (f) EWSR1 gene fusion (fusion of EWSR1 exon 7 to FLI1 exon 6). © 2014 British Association of Dermatologists
lesions in the lymph nodes and bone disappeared 10 months after treatment, and the patient continues to exhibit complete remission. Primary cutaneous ES, also known as superficial or dermal ES, was first reported in 1975.3 Since then, only a few cases or small series have been reported. The prognosis of primary cutaneous ES seems to be better than that in patients with bone ES. Delaplace et al.4 described the 10-year probability of survival to be 91% for patients with primary cutaneous ES, although the 5-year survival has been reported to be 68% for localized bone ES and 39% for metastatic ES.5 This may be associated with earlier diagnoses and the detection of smaller tumours in the setting of primary cutaneous ES.6,7 The current recommendations for the treatment of both primary cutaneous ES and bone ES are the same, despite the fact that the prognosis of primary cutaneous ES is superior to that of bone ES. Therefore, Delaplace et al.4 proposed that the value of combining radiotherapy and chemotherapy with a wide surgical margin for primary cutaneous ES should be reconsidered. In this case, although the tumour was initially localized in the dermis and we performed complete removal with the administration of chemotherapy, the patient developed multiple metastases, and additional chemotherapy and autologous peripheral blood stem cell transplantation were required to achieve the complete remission. The tumour cells might invade dermal vessels, although we could not see this in the tissue specimens.
(a)
(b)
(c)
(d)
(e)
(f)
British Journal of Dermatology (2014) 171, pp657–678
662 Correspondence 1
(a)
Department of Dermatology and Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan 3 Department of Pathology, Kanazawa Medical University, Kanazawa, Japan E-mail: [email protected] 2
M. MIZAWA1 T. MAKINO1 O. NORISUGI1 H. HARA1 K. SHIMIZU1 K. NOMURA2 H. KANEGANE2 T. NOJIMA3 T. SHIMIZU1
References
(b)
(c)
1 Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc 1921; 21:17. 2 Jedlicka P. Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions. Int J Clin Exp Pathol 2010; 3:338–47. 3 Angervall L, Enzinger FM. Extraskeletal neoplasm resembling Ewing’s sarcoma. Cancer 1975; 36:240–51. 4 Delaplace M, Lhommet C, de Pinieux G et al. Primary cutaneous Ewing sarcoma: a systematic review focused on treatment and outcome. Br J Dermatol 2012; 166:721–6. 5 Esiashvili N, Goodman M, Marcus RB Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 2008; 30:425–30. 6 Cotterill SJ, Ahrens S, Paulussen M et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 2000; 18:3108–14. 7 Ladenstein R, P€ otschger U, Le Deley MC et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010; 28:3284–91. Funding sources: none. Conflicts of interest: none declared.
Two cases of nicorandil-induced ulceration mimicking skin malignancy DOI: 10.1111/bjd.12978
Fig 2. (a) Positron emission tomography/computed tomography showing high uptake in the bilateral cervical lymph nodes (arrowheads). (b) Coronal T2-weighted short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) findings demonstrating a region with high signal intensity in the left ilium (arrowhead). (c) Coronal T2-weighted STIR MRI findings showing a region with high signal intensity in the right femur (arrowhead).
Generally, we agree with the need to reconsider the therapeutic protocol in the setting of primary cutaneous ES; however, clinicians should also pay attention to the possibility that multiple metastases may develop even in patients with primary cutaneous ES. British Journal of Dermatology (2014) 171, pp657–678
DEAR EDITOR, Cutaneous ulceration caused by nicorandil is well described at perianal, anal, peristomal, oral, vulval and cutaneous sites,1–6 and most recently on the conjunctiva.7 We present the first reported cases of nicorandil-induced ulceration of the temple and the nasal mucosa, which were referred as possible skin malignancies. Patient 1 was an 88-year-old man with a 3-week history of a painful ulcer on his left temple. He had been receiving nicorandil 20 mg twice daily for the previous 2 years. Examination of the left temple revealed a 15-mm discoid, punched-out ulcer with a purulent base and an erythematous rim (Fig. 1). An incisional biopsy from the ulcer edge showed inflammatory © 2014 British Association of Dermatologists
the eponym ‘Nakajo–Nishimura syndrome’ as the unifying nomenclature of these three syndromes. However, avoidance of eponyms has become the public tendency in recent years and an acronym is preferred which summarizes information of the disease. Nevertheless, the acronyms JMP and CANDLE seem to represent only limited aspects of this disease, the advanced phenotypes and the pathological features, respectively. Indeed, Online Mendelian Inheritance in Man (OMIM) #256040, in which the designation ‘Nakajo syndrome’ has long been registered until recently, now includes all three syndromes under the new designation ‘autoinflammation, lipodystrophy and dermatosis (ALDD) syndrome’. Furthermore, a new conceptual acronym ‘proteasome-associated autoinflammatory syndromes (PRAAS)’ has recently been proposed as the umbrella term for these three syndromes.10 However, to apply this designation, proteasome dysfunction due to the novel mutation should be evident. Collectively, we believe that it would be both appropriate and desirable to discuss the distinction of these syndromes from the genetic and clinical aspects and, if they are really included in the same entity, to select the most suitable designation for the definition. 1
Department of Dermatology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan 2 Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayamashi, Tokyo 189-0002, Japan 3 Department of Pediatrics and Child Health, Nihon University School of Medicine, Nihon University Itabashi Hospital, 30-1, Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan Correspondence: Nobuo Kanazawa. E-mail: [email protected]
N. KANAZAWA1 K. KUNIMOTO1 N. ISHII2 Y. INAMO3 F. FURUKAWA1
References 1 Kluk J, Rustin M, Brogan PA et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a report of a novel mutation and review of the literature. Br J Dermatol 2014; 170:215–17. 2 Torrelo A, Patel S, Colmenero I et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol 2010; 62:489–95. 3 Kunimoto K, Kimura A, Uede K et al. A new infant case of NakajoNishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. Dermatology 2013; 227:26–30. 4 Garg A, Hernandez MD, Sousa AB et al. An autosomal recessive syndrome of joint contracture, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J Clin Endcrinol Metab 2010; 95:E48–63. 5 Agarwal AK, Xing C, DeMartino GN et al. PSMB8 encoding the b5i proteasome subunit is mutated in joint contractures, muscle
British Journal of Dermatology (2014) 171, pp657–678
6
7
8
9
10
atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 2010; 87:866–72. Kitano Y, Matsunaga E, Morimoto T et al. A syndrome with nodular erythema, elongated and thickened fingers, and emaciation. Arch Dermatol 1985; 121:1053–6. Arima K, Kinoshita A, Mishima H et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci USA 2011; 108:14914–19. Liu Y, Ramot Y, Torrelo A et al. Mutations in PSMB8 cause CANDLE syndrome with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 2012; 64:895–907. Messia V, Pardeo M, Nicolai R et al. P02-16 – a novel PSMB8 mutation causing candle syndrome. Pediatr Rheumatol 2013; 11(Suppl. 1):A123. McDermott A, Jesus AA, Liu Y et al. A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations. J Am Acad Dermatol 2013; 69:e29–32.
Funding sources: This work was supported by a grant from the Japan Society for Promotion of Science (N.K. and K.K.) and Japan Ministry of Health, Labor and Welfare. Conflicts of interest: none declared.
Primary cutaneous Ewing sarcoma following metastasis to the bone and lymph nodes DOI: 10.1111/bjd.12979 DEAR EDITOR, Ewing sarcoma (ES) is a rare malignant round-cell tumour that primarily affects the skeletal system and is commonly diagnosed in children and young adults. It was first described in 1921.1 ES tumours consist of small, round cells that mostly express CD99, and that are characterized by a specific chromosomal translocation involving the EWSR1 gene on chromosome 22, with an erythroblastosis virus-transforming gene (in most cases, the FLI1 gene), thus resulting in a fusion oncogene.2 A 9-year-old Japanese girl found a subcutaneous tumour measuring 15 9 20 cm on the left side of her upper back 1 month prior to admission. She visited a dermatological clinic because the lesion increased slightly in size. At the clinic, the tumour was found to be enucleated, and the histological findings suggested a possible diagnosis of ES. Therefore, the patient was admitted to our hospital for further examination and treatment. Physical examination showed only a surgical scar on the left side of the patient’s upper back. No regional lymph node involvement was detectable. The findings of a blood test were within normal limits. Histological examination revealed a tumour, composed of round cells exhibiting dysplastic changes, within the dermis (Fig. 1a). Mitotic cells were also observed (Fig. 1b). Microscopic vascular invasion of tumour cells was not observed. Immunohistochemical study showed that most of the tumour cells expressed CD99 (Fig. 1c) and vimentin (Fig. 1d). Fluorescence in situ hybridization analysis using an © 2014 British Association of Dermatologists
Correspondence 661
EWSR1 break-apart probe detected translocation of EWSR1 (Fig. 1e). Furthermore, reverse-transcriptase polymerase chain reaction analysis and direct sequencing identified EWSR1 gene fusion (the fusion of EWSR1 exon 7 to FLI1 exon 6) (Fig. 1f). Positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) of the whole body did not detect any abnormalities in the lymph nodes or internal organs. No bone marrow involvement was observed. Based on these findings, the patient was diagnosed with primary cutaneous ES. An extensive excision was performed with a 5-cm surgical margin from the surgical scar, and the patient received two cycles of chemotherapy, including cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide and etoposide. However, 8 months after the administration of chemotherapy, PET/CT and enhanced MRI detected multiple lesions in the bilateral cervical lymph nodes, left ilium and right femur, suggesting multiple metastases (Fig. 2a–c). Although tissue specimens obtained from the left ilium showed only a few abnormal cells and did not exhibit findings suggestive of metastases of ES, eight additional cycles of chemotherapy were administered. Most of the lesions in the lymph nodes and bone reduced in size, although they did not disappear completely. Therefore, an autologous peripheral blood stem cell transplantation was performed following the administration of high-dose chemotherapy, which included melphalan, etoposide and carboplatin. The
Fig 1. (a) Histological examination revealed a tumour within the dermis (haematoxylin and eosin stain). (b) The tumour was composed of basaloid round cells with severe dysplasia (haematoxylin and eosin stain, original magnification 200 9). The expression of (c) CD99 and (d) vimentin was observed in the infiltrated tumour cells (original magnification 200 9). (e) Fluorescence in situ hybridization/EWSR1 with break-apart positive for the translocation of EWSR1. (f) EWSR1 gene fusion (fusion of EWSR1 exon 7 to FLI1 exon 6). © 2014 British Association of Dermatologists
lesions in the lymph nodes and bone disappeared 10 months after treatment, and the patient continues to exhibit complete remission. Primary cutaneous ES, also known as superficial or dermal ES, was first reported in 1975.3 Since then, only a few cases or small series have been reported. The prognosis of primary cutaneous ES seems to be better than that in patients with bone ES. Delaplace et al.4 described the 10-year probability of survival to be 91% for patients with primary cutaneous ES, although the 5-year survival has been reported to be 68% for localized bone ES and 39% for metastatic ES.5 This may be associated with earlier diagnoses and the detection of smaller tumours in the setting of primary cutaneous ES.6,7 The current recommendations for the treatment of both primary cutaneous ES and bone ES are the same, despite the fact that the prognosis of primary cutaneous ES is superior to that of bone ES. Therefore, Delaplace et al.4 proposed that the value of combining radiotherapy and chemotherapy with a wide surgical margin for primary cutaneous ES should be reconsidered. In this case, although the tumour was initially localized in the dermis and we performed complete removal with the administration of chemotherapy, the patient developed multiple metastases, and additional chemotherapy and autologous peripheral blood stem cell transplantation were required to achieve the complete remission. The tumour cells might invade dermal vessels, although we could not see this in the tissue specimens.
(a)
(b)
(c)
(d)
(e)
(f)
British Journal of Dermatology (2014) 171, pp657–678
662 Correspondence 1
(a)
Department of Dermatology and Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan 3 Department of Pathology, Kanazawa Medical University, Kanazawa, Japan E-mail: [email protected] 2
M. MIZAWA1 T. MAKINO1 O. NORISUGI1 H. HARA1 K. SHIMIZU1 K. NOMURA2 H. KANEGANE2 T. NOJIMA3 T. SHIMIZU1
References
(b)
(c)
1 Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc 1921; 21:17. 2 Jedlicka P. Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions. Int J Clin Exp Pathol 2010; 3:338–47. 3 Angervall L, Enzinger FM. Extraskeletal neoplasm resembling Ewing’s sarcoma. Cancer 1975; 36:240–51. 4 Delaplace M, Lhommet C, de Pinieux G et al. Primary cutaneous Ewing sarcoma: a systematic review focused on treatment and outcome. Br J Dermatol 2012; 166:721–6. 5 Esiashvili N, Goodman M, Marcus RB Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 2008; 30:425–30. 6 Cotterill SJ, Ahrens S, Paulussen M et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 2000; 18:3108–14. 7 Ladenstein R, P€ otschger U, Le Deley MC et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010; 28:3284–91. Funding sources: none. Conflicts of interest: none declared.
Two cases of nicorandil-induced ulceration mimicking skin malignancy DOI: 10.1111/bjd.12978
Fig 2. (a) Positron emission tomography/computed tomography showing high uptake in the bilateral cervical lymph nodes (arrowheads). (b) Coronal T2-weighted short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) findings demonstrating a region with high signal intensity in the left ilium (arrowhead). (c) Coronal T2-weighted STIR MRI findings showing a region with high signal intensity in the right femur (arrowhead).
Generally, we agree with the need to reconsider the therapeutic protocol in the setting of primary cutaneous ES; however, clinicians should also pay attention to the possibility that multiple metastases may develop even in patients with primary cutaneous ES. British Journal of Dermatology (2014) 171, pp657–678
DEAR EDITOR, Cutaneous ulceration caused by nicorandil is well described at perianal, anal, peristomal, oral, vulval and cutaneous sites,1–6 and most recently on the conjunctiva.7 We present the first reported cases of nicorandil-induced ulceration of the temple and the nasal mucosa, which were referred as possible skin malignancies. Patient 1 was an 88-year-old man with a 3-week history of a painful ulcer on his left temple. He had been receiving nicorandil 20 mg twice daily for the previous 2 years. Examination of the left temple revealed a 15-mm discoid, punched-out ulcer with a purulent base and an erythematous rim (Fig. 1). An incisional biopsy from the ulcer edge showed inflammatory © 2014 British Association of Dermatologists
