Commentaries 7 Webber SA, Wurm EM, Douglas NC et al. Effectiveness and limitations of reflectance confocal microscopy in detecting persistence of basal cell carcinomas: a preliminary study. Australas J Dermatol 2011; 52:179–85. 8 Longo C, Farnetani F, Ciardo S et al. Is confocal microscopy a valuable tool in diagnosing nodular lesions? A study of 140 cases. Br J Dermatol 2013; 169:58–67. 9 Hoogedoorn L, Peppelman M, van de Kerkhof PC et al. The value of in vivo reflectance confocal microscopy in the diagnosis and monitoring of inflammatory and infectious skin diseases: a systematic review. Br J Dermatol 2015; 172:1222–48.
Associations between Merkel cell carcinoma and Merkel cell polyomavirus DOI: 10.1111/bjd.13925 ORIGINAL ARTICLE, p 42 Merkel cell carcinomas (MCCs) are rare but highly aggressive neuroendocrine carcinomas of the skin predominantly affecting elderly and immunosuppressed patients.1,2 Their incidence has tripled worldwide during the last three decades. Considerable advance in elucidating their pathogenesis has been achieved since 2008 when a novel polyomavirus, the Merkel cell virus (MCV), was identified and detected in a large percentage of MCCs.3 The MCV is thought to be causative for tumorigenesis of MCCs although the underlying oncogenic mechanisms have not yet been fully clarified.1,2 MCV DNA is clonally integrated into the genome of Merkel carcinoma cells, with identical integration patterns in primary tumours and their metastases. The viral genome encodes three oncoproteins, the large T (LT), the small T (sT) and the 57-kT antigen, and three capsid proteins (VP1, VP2 and VP3). Genomic integration of MCV DNA is systematically associated with truncating mutations in the sequence encoding the LT antigen, resulting in loss of the domains required for viral DNA replication and binding of the p53 protein but increased binding affinity for Rb. The sT antigen activates Akt-mTOR signalling by binding to the protein phosphatase 2A, a pathway critical for survival of tumour cells. MCV DNA is detected in 70–100% of MCCs and with lower prevalence in other types of tumours, e.g. nonmelanoma skin cancers.4 The prevalence of latent MCV infections is high, as up to 80% of the sera from healthy adults exhibit MCV seropositivity5 and low amounts of MCV DNA can be frequently detected in cutaneous swabs from healthy individuals. For tumorigenesis of MCCs, loss of immunosurveillance and clonal integration of the MCV DNA into the cellular genome are required together with additional cellular events.1,2 In this issue of the BJD, Santos-Juanes et al.6 present a systematic review and meta-analysis on the correlation between MCCs and MCV. Twenty-two studies investigating the prevalence of MCV in cutaneous MCCs and control samples with © 2015 British Association of Dermatologists
7
polymerase chain reaction (PCR) technique were included. Global proportions of MCV-positive samples were 079 in the MCC group and 012 in the control groups. The pooled relative risk from random effects analysis for the association between MCCs and MCV was 632. These findings clearly support the association between MCC and MCV, although the studies included in the meta-analysis were heterogeneous. Prevalence rates of MCV DNA reported in different studies may vary depending on the PCR technique and primers used. In addition, the virus can be detected by immunohistochemistry with highly sensitive and specific antibodies against the LT antigen.7 The prognostic significance of MCV is still a matter of debate. According to some studies, the presence of MCV DNA had no influence on the clinical course of patients with MCC,8 whereas other studies suggested a prognostically favourable impact of a high number of viral DNA copies.9 Patients with MCC with high VP1 antibody titres appear to have a better prognosis than others.10 By contrast, persistence or recurrence of antibodies against the LT antigen after treatment has been associated with poor prognosis. Further work is required to fully resolve the prognostic significance of MCV as well as its clinical and therapeutic implications. Studies investigating MCV oncoproteins as novel therapeutic targets are already ongoing1,2 and will hopefully contribute to improving the unfavourable prognosis of advanced and metastasizing MCCs.
Funding sources No external funding.
Conflicts of interest None declared. Department of Dermatology, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany E-mail: [email protected]
W.K. PEITSCH
References 1 Hughes MP, Hardee ME, Cornelius LA et al. Merkel cell carcinoma: epidemiology, target, and therapy. Curr Dermatol Rep 2014; 3: 46–53. 2 Samimi M, Gardair C, Nicol JT et al. Merkel cell polyomavirus in Merkel cell carcinoma: clinical and therapeutic perspectives. Semin Oncol 2015; 42:347–58. 3 Feng H, Shuda M, Chang Y et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319: 1096–100. 4 Scola N, Wieland U, Silling S et al. Prevalence of human polyomaviruses in common and rare types of non-Merkel cell carcinoma skin cancer. Br J Dermatol 2012; 167:1315–20. British Journal of Dermatology (2015) 173, pp6–18
8 Commentaries 5 Tolstov YL, Pastrana DV, Feng H et al. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer 2009; 125:1250–6. 6 Santos-Juanes J, Fernandez-Vega I, Fuentes N et al. Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol 2015; 173:42–9. 7 Rodig SJ, Cheng J, Wardzala J et al. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest 2012; 122:4645–53. 8 Schrama D, Peitsch WK, Zapatka M et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol 2011; 131:1631–8. 9 Bhatia K, Goedert JJ, Modali R et al. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int J Cancer 2010; 126:2240–6. 10 Touze A, Le Bidre E, Laude H et al. High levels of antibodies against Merkel cell polyomavirus identify a subset of patients with Merkel cell carcinoma with better clinical outcome. J Clin Oncol 2011; 29:1612–9.
using RCM showed abnormally elevated numbers of DF in PPR9–11 and also in pityriasis folliculorum.11 DF densities found with RCM far exceed those found using SSSB and whether this reflects a higher sensitivity is still controversial.12,13 It seems reasonable to assume that a direct comparison of absolute numbers of DF between ex vivo (SSSB) and in vivo (RCM) is not realistic. Instead, we recently showed that RCM is equivalent to SSSB to identify populations with a low number of DF and patients with high numbers of DF.14 Sattler et al.1 now add an important contribution to the wealth of data regarding RCM, rosacea and DF. They report a statistically significant reduction of the density of DF in the facial skin of patients with rosacea treated by oral tetracyclines and topical metronidazole, with a parallel clinical improvement. Future studies should aim at determining if there is a statistical correlation between the magnitude of DF decrease and clinical efficacy, and the chronological link, as expected, if DF is a major player in PPR. Given its possibilities of quantitative assessment and time-course monitoring of DF infestation, RCM will probably be a new key for assessing definitively the role of Demodex in rosacea.
Reflectance confocal microscopy: a new key for assessing the role of Demodex in rosacea?
Funding sources No external funding.
DOI: 10.1111/bjd.13903
Conflicts of interest
ORIGINAL ARTICLE, p 69
None declared. 1
In this issue of the BJD, Sattler et al. report the interest of reflectance confocal microscopy (RCM) to monitor Demodex density in rosacea before and after treatment. Rosacea is a common, disabling, and difficult to cure facial skin disorder. Novel treatments are scarce as the pathogenesis of the disease is poorly understood. Demodex folliculorum (DF), a saprophytic ectoparasite of the human hair follicle, has been extensively, although not conclusively, implicated in the pathogenesis of papulopustular rosacea (PPR), either as a causative agent, or as a reservoir for other micro-organisms.2,3 The role of DF in PPR was mostly investigated through skin scrapings or superficial standardized skin biopsies (SSSB). While SSSB seems more accurate than scrapings,4 its limitations are recognized.5 Using these techniques, it was shown that DF density is abnormally high in these patients, with a diagnosis threshold of > 5 mites cm 2. Two trials comparing metronidazole vs. permethrin6 or benzoyl peroxide-erythromycin7 for PPR reported a decrease in positive DF scrapings after treatment. RCM is a noninvasive, real-time, office-based, repeatable imaging device that provides horizontal (en face) serial sections of the skin. The field of view (up to 8 9 8 mm), resolution (25 lm) and imaging depth (200 lm) of RCM are mostly suitable for DF (~300 lm length), providing characteristic annular cross-section images of the elliptic parasite, and live recordings of DF movements.8 Three recent studies
British Journal of Dermatology (2015) 173, pp6–18
Department of Dermatology, Clinical Research Centre, Nice, France E-mail: [email protected]
P. BAHADORAN
References 1 Sattler EC, Hoffmann VS, Ruzicka T et al. Reflectance confocal microscopy for monitoring the density of Demodex mites in patients with rosacea before and after treatment. Br J Dermatol 2015; 173:69–75. 2 Kligman AM, Christensen MS. Demodex folliculorum: requirements for understanding its role in human skin disease. J Invest Dermatol 2011; 131:8–10. 3 Holmes AD. Potential role of microorganisms in the pathogenesis of rosacea. J Am Acad Dermatol 2013; 69:1025–32. 4 Asßkin U, Secßkin D. Comparison of the two techniques for measurement of the density of Demodex folliculorum: standardized skin surface biopsy and direct microscopic examination. Br J Dermatol 2010; 162:1124–6. 5 Forton F, Song M. Limitations of standardized skin surface biopsy in measurement of the density of Demodex folliculorum. A case report. Br J Dermatol 1998; 139:697–700. 6 Kocßak M, Yagli S, Vahapoglu G, Eksßioglu M. Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea. A randomized double-blind placebo-controlled study. Dermatology 2002; 205:265–70. 7 Ozt€ urkcan S, Ermertcan AT, Sahin MT, Afsßar FS. Efficiency of benzoyl peroxide-erythromycin gel in comparison with metroni-
© 2015 British Association of Dermatologists
Associations between Merkel cell carcinoma and Merkel cell polyomavirus DOI: 10.1111/bjd.13925 ORIGINAL ARTICLE, p 42 Merkel cell carcinomas (MCCs) are rare but highly aggressive neuroendocrine carcinomas of the skin predominantly affecting elderly and immunosuppressed patients.1,2 Their incidence has tripled worldwide during the last three decades. Considerable advance in elucidating their pathogenesis has been achieved since 2008 when a novel polyomavirus, the Merkel cell virus (MCV), was identified and detected in a large percentage of MCCs.3 The MCV is thought to be causative for tumorigenesis of MCCs although the underlying oncogenic mechanisms have not yet been fully clarified.1,2 MCV DNA is clonally integrated into the genome of Merkel carcinoma cells, with identical integration patterns in primary tumours and their metastases. The viral genome encodes three oncoproteins, the large T (LT), the small T (sT) and the 57-kT antigen, and three capsid proteins (VP1, VP2 and VP3). Genomic integration of MCV DNA is systematically associated with truncating mutations in the sequence encoding the LT antigen, resulting in loss of the domains required for viral DNA replication and binding of the p53 protein but increased binding affinity for Rb. The sT antigen activates Akt-mTOR signalling by binding to the protein phosphatase 2A, a pathway critical for survival of tumour cells. MCV DNA is detected in 70–100% of MCCs and with lower prevalence in other types of tumours, e.g. nonmelanoma skin cancers.4 The prevalence of latent MCV infections is high, as up to 80% of the sera from healthy adults exhibit MCV seropositivity5 and low amounts of MCV DNA can be frequently detected in cutaneous swabs from healthy individuals. For tumorigenesis of MCCs, loss of immunosurveillance and clonal integration of the MCV DNA into the cellular genome are required together with additional cellular events.1,2 In this issue of the BJD, Santos-Juanes et al.6 present a systematic review and meta-analysis on the correlation between MCCs and MCV. Twenty-two studies investigating the prevalence of MCV in cutaneous MCCs and control samples with © 2015 British Association of Dermatologists
7
polymerase chain reaction (PCR) technique were included. Global proportions of MCV-positive samples were 079 in the MCC group and 012 in the control groups. The pooled relative risk from random effects analysis for the association between MCCs and MCV was 632. These findings clearly support the association between MCC and MCV, although the studies included in the meta-analysis were heterogeneous. Prevalence rates of MCV DNA reported in different studies may vary depending on the PCR technique and primers used. In addition, the virus can be detected by immunohistochemistry with highly sensitive and specific antibodies against the LT antigen.7 The prognostic significance of MCV is still a matter of debate. According to some studies, the presence of MCV DNA had no influence on the clinical course of patients with MCC,8 whereas other studies suggested a prognostically favourable impact of a high number of viral DNA copies.9 Patients with MCC with high VP1 antibody titres appear to have a better prognosis than others.10 By contrast, persistence or recurrence of antibodies against the LT antigen after treatment has been associated with poor prognosis. Further work is required to fully resolve the prognostic significance of MCV as well as its clinical and therapeutic implications. Studies investigating MCV oncoproteins as novel therapeutic targets are already ongoing1,2 and will hopefully contribute to improving the unfavourable prognosis of advanced and metastasizing MCCs.
Funding sources No external funding.
Conflicts of interest None declared. Department of Dermatology, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany E-mail: [email protected]
W.K. PEITSCH
References 1 Hughes MP, Hardee ME, Cornelius LA et al. Merkel cell carcinoma: epidemiology, target, and therapy. Curr Dermatol Rep 2014; 3: 46–53. 2 Samimi M, Gardair C, Nicol JT et al. Merkel cell polyomavirus in Merkel cell carcinoma: clinical and therapeutic perspectives. Semin Oncol 2015; 42:347–58. 3 Feng H, Shuda M, Chang Y et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319: 1096–100. 4 Scola N, Wieland U, Silling S et al. Prevalence of human polyomaviruses in common and rare types of non-Merkel cell carcinoma skin cancer. Br J Dermatol 2012; 167:1315–20. British Journal of Dermatology (2015) 173, pp6–18
8 Commentaries 5 Tolstov YL, Pastrana DV, Feng H et al. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer 2009; 125:1250–6. 6 Santos-Juanes J, Fernandez-Vega I, Fuentes N et al. Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol 2015; 173:42–9. 7 Rodig SJ, Cheng J, Wardzala J et al. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest 2012; 122:4645–53. 8 Schrama D, Peitsch WK, Zapatka M et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol 2011; 131:1631–8. 9 Bhatia K, Goedert JJ, Modali R et al. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int J Cancer 2010; 126:2240–6. 10 Touze A, Le Bidre E, Laude H et al. High levels of antibodies against Merkel cell polyomavirus identify a subset of patients with Merkel cell carcinoma with better clinical outcome. J Clin Oncol 2011; 29:1612–9.
using RCM showed abnormally elevated numbers of DF in PPR9–11 and also in pityriasis folliculorum.11 DF densities found with RCM far exceed those found using SSSB and whether this reflects a higher sensitivity is still controversial.12,13 It seems reasonable to assume that a direct comparison of absolute numbers of DF between ex vivo (SSSB) and in vivo (RCM) is not realistic. Instead, we recently showed that RCM is equivalent to SSSB to identify populations with a low number of DF and patients with high numbers of DF.14 Sattler et al.1 now add an important contribution to the wealth of data regarding RCM, rosacea and DF. They report a statistically significant reduction of the density of DF in the facial skin of patients with rosacea treated by oral tetracyclines and topical metronidazole, with a parallel clinical improvement. Future studies should aim at determining if there is a statistical correlation between the magnitude of DF decrease and clinical efficacy, and the chronological link, as expected, if DF is a major player in PPR. Given its possibilities of quantitative assessment and time-course monitoring of DF infestation, RCM will probably be a new key for assessing definitively the role of Demodex in rosacea.
Reflectance confocal microscopy: a new key for assessing the role of Demodex in rosacea?
Funding sources No external funding.
DOI: 10.1111/bjd.13903
Conflicts of interest
ORIGINAL ARTICLE, p 69
None declared. 1
In this issue of the BJD, Sattler et al. report the interest of reflectance confocal microscopy (RCM) to monitor Demodex density in rosacea before and after treatment. Rosacea is a common, disabling, and difficult to cure facial skin disorder. Novel treatments are scarce as the pathogenesis of the disease is poorly understood. Demodex folliculorum (DF), a saprophytic ectoparasite of the human hair follicle, has been extensively, although not conclusively, implicated in the pathogenesis of papulopustular rosacea (PPR), either as a causative agent, or as a reservoir for other micro-organisms.2,3 The role of DF in PPR was mostly investigated through skin scrapings or superficial standardized skin biopsies (SSSB). While SSSB seems more accurate than scrapings,4 its limitations are recognized.5 Using these techniques, it was shown that DF density is abnormally high in these patients, with a diagnosis threshold of > 5 mites cm 2. Two trials comparing metronidazole vs. permethrin6 or benzoyl peroxide-erythromycin7 for PPR reported a decrease in positive DF scrapings after treatment. RCM is a noninvasive, real-time, office-based, repeatable imaging device that provides horizontal (en face) serial sections of the skin. The field of view (up to 8 9 8 mm), resolution (25 lm) and imaging depth (200 lm) of RCM are mostly suitable for DF (~300 lm length), providing characteristic annular cross-section images of the elliptic parasite, and live recordings of DF movements.8 Three recent studies
British Journal of Dermatology (2015) 173, pp6–18
Department of Dermatology, Clinical Research Centre, Nice, France E-mail: [email protected]
P. BAHADORAN
References 1 Sattler EC, Hoffmann VS, Ruzicka T et al. Reflectance confocal microscopy for monitoring the density of Demodex mites in patients with rosacea before and after treatment. Br J Dermatol 2015; 173:69–75. 2 Kligman AM, Christensen MS. Demodex folliculorum: requirements for understanding its role in human skin disease. J Invest Dermatol 2011; 131:8–10. 3 Holmes AD. Potential role of microorganisms in the pathogenesis of rosacea. J Am Acad Dermatol 2013; 69:1025–32. 4 Asßkin U, Secßkin D. Comparison of the two techniques for measurement of the density of Demodex folliculorum: standardized skin surface biopsy and direct microscopic examination. Br J Dermatol 2010; 162:1124–6. 5 Forton F, Song M. Limitations of standardized skin surface biopsy in measurement of the density of Demodex folliculorum. A case report. Br J Dermatol 1998; 139:697–700. 6 Kocßak M, Yagli S, Vahapoglu G, Eksßioglu M. Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea. A randomized double-blind placebo-controlled study. Dermatology 2002; 205:265–70. 7 Ozt€ urkcan S, Ermertcan AT, Sahin MT, Afsßar FS. Efficiency of benzoyl peroxide-erythromycin gel in comparison with metroni-
© 2015 British Association of Dermatologists
