BJD
British Journal of Dermatology
C O M ME N T A R I E S
Reflectance confocal microscopy for better management of cutaneous pink lesions DOI: 10.1111/bjd.13820 ORIGINAL ARTICLE, p 31 Insights into the usefulness of new techniques for noninvasive diagnosis of skin lesions in daily practice are always welcome1 and this is even more valid in the case of solitary cutaneous ‘pink lesions’, which represent one of the most intriguing and challenging diagnostic dilemmas in dermatology. Although dermoscopy is useful in the differentiation of pink skin lesions, in specific cases it lacks distinctive diagnostic criteria even in experienced hands.2 Obviously missing the diagnosis of an amelanotic melanoma is the elephant in the room and pitfalls in the clinical and dermoscopic diagnosis of pink lesions are legendary. Reflectance confocal microscopy (RCM) is a relatively new noninvasive technique demonstrated to increase specificity in the diagnosis of skin cancer.3 Due to its high lateral resolution and quasi-histology image quality, RCM opens up a new dimension in the presurgical interpretation of pink lesions.4 In this issue of the BJD, Caterina Longo and colleagues describe, in a meticulous and rigorous review, the RCM features for the differential diagnosis of solitary pink lesions.5 The authors detail the advantages of the use of RCM in fast, real-time identification of the melanocytic, epithelial or vascular differentiation of a given lesion. However, they also describe how the absence of pigment decreases the quality of confocal imaging, with diagnostic features becoming subtle and difficult to detect. In this context, we cannot emphasize enough the relevance of formal training in RCM in order to minimize human error in diagnosis, which is well known in conventional pathology and will certainly also occur with RCM.6 Because diagnostic RCM has come into use only recently, this aspect has not been widely published.7 In addition, there are a few inherent reasons making diagnostic confocal clues difficult to detect, including acanthosis, ulceration and hyperkeratosis characterizing some pink lesions, such as seborrhoeic keratoses, basal cell carcinomas or Spitz naevi, as well as some inflammatory skin conditions.8 These issues can be addressed by preselection of the lesions or pretreatment with keratolytic ointments; however, they remain a drawback to the wider implementation of RCM. Inflammatory skin diseases, although not normally presenting as single lesions, must be kept in consideration in the differential diagnosis with pink neoplastic tumours. A typical example for this differential diagnostic predicament is a solitary psoriasis lesion vs. Bowen disease on the lower leg. While assessment of inflammatory skin diseases with RCM is an increasing topic of interest, well-designed clinical studies are still necessary to create adequate guidelines and
6
British Journal of Dermatology (2015) 173, pp6–18
protocols for further implementation of RCM in clinical practice.9 Despite the limitations of both RCM and dermoscopy, their synergistic use will increase the diagnostic accuracy of solitary pink lesions with better identification of malignant neoplasms and ultimately will improve patient experience and reduce skin cancer morbidity and, hopefully, mortality. In conclusion, from a purely selfish dermatologists’ perspective, embracing new imaging technologies for diagnosing and managing neoplastic and inflammatory skin diseases is necessary in order to be at the forefront of the exciting technology revolution in medicine in the 21st century. In this spirit we commend Caterina Longo and colleagues for their insightful review.
Conflicts of interest None declared. 1
San Gallicano Dermatological Institute, IRCCS, IFO, Via Chianesi 53, 00144 Rome, Italy 2 Dermatology Research Centre, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia 3 Department of Dermatology, Princess Alexandra Hospital, Brisbane, QLD, Australia E-mail: [email protected] ORCID: M.A.: orcid.org/0000-00025772-4937; H.P.S.: orcid.org/00000002-4770-561X
M . A R D I G O 1 H.P. SOYER2,3
References 1 Soyer HP, Prow TW. Reflectance confocal microscopy in the diagnosis of nodular skin lesions. Br J Dermatol 2013; 169:4–5. 2 Giacomel J, Zalaudek I. Pink lesions. Dermatol Clin 2013; 31:649–78. 3 Guitera P, Menzies SW, Longo C et al. In vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a twostep method: analysis of 710 consecutive clinically equivocal cases. J Invest Dermatol 2012; 132:2386–94. 4 Braga JC, Scope A, Klaz I et al. The significance of reflectance confocal microscopy in the assessment of solitary pink skin lesions. J Am Acad Dermatol 2009; 61:230–41. 5 Longo C, Moscarella E, Argenziano G et al. Reflectance confocal microscopy in the diagnosis of solitary pink skin tumors: review of diagnostic clues. Br J Dermatol 2015; 173:31–41. 6 Zarbo RJ, Meier FA, Raab SS. Error detection in anatomic pathology. Arch Pathol Lab Med 2005; 129:1237–45.
© 2015 British Association of Dermatologists
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
British Journal of Dermatology
C O M ME N T A R I E S
Reflectance confocal microscopy for better management of cutaneous pink lesions DOI: 10.1111/bjd.13820 ORIGINAL ARTICLE, p 31 Insights into the usefulness of new techniques for noninvasive diagnosis of skin lesions in daily practice are always welcome1 and this is even more valid in the case of solitary cutaneous ‘pink lesions’, which represent one of the most intriguing and challenging diagnostic dilemmas in dermatology. Although dermoscopy is useful in the differentiation of pink skin lesions, in specific cases it lacks distinctive diagnostic criteria even in experienced hands.2 Obviously missing the diagnosis of an amelanotic melanoma is the elephant in the room and pitfalls in the clinical and dermoscopic diagnosis of pink lesions are legendary. Reflectance confocal microscopy (RCM) is a relatively new noninvasive technique demonstrated to increase specificity in the diagnosis of skin cancer.3 Due to its high lateral resolution and quasi-histology image quality, RCM opens up a new dimension in the presurgical interpretation of pink lesions.4 In this issue of the BJD, Caterina Longo and colleagues describe, in a meticulous and rigorous review, the RCM features for the differential diagnosis of solitary pink lesions.5 The authors detail the advantages of the use of RCM in fast, real-time identification of the melanocytic, epithelial or vascular differentiation of a given lesion. However, they also describe how the absence of pigment decreases the quality of confocal imaging, with diagnostic features becoming subtle and difficult to detect. In this context, we cannot emphasize enough the relevance of formal training in RCM in order to minimize human error in diagnosis, which is well known in conventional pathology and will certainly also occur with RCM.6 Because diagnostic RCM has come into use only recently, this aspect has not been widely published.7 In addition, there are a few inherent reasons making diagnostic confocal clues difficult to detect, including acanthosis, ulceration and hyperkeratosis characterizing some pink lesions, such as seborrhoeic keratoses, basal cell carcinomas or Spitz naevi, as well as some inflammatory skin conditions.8 These issues can be addressed by preselection of the lesions or pretreatment with keratolytic ointments; however, they remain a drawback to the wider implementation of RCM. Inflammatory skin diseases, although not normally presenting as single lesions, must be kept in consideration in the differential diagnosis with pink neoplastic tumours. A typical example for this differential diagnostic predicament is a solitary psoriasis lesion vs. Bowen disease on the lower leg. While assessment of inflammatory skin diseases with RCM is an increasing topic of interest, well-designed clinical studies are still necessary to create adequate guidelines and
6
British Journal of Dermatology (2015) 173, pp6–18
protocols for further implementation of RCM in clinical practice.9 Despite the limitations of both RCM and dermoscopy, their synergistic use will increase the diagnostic accuracy of solitary pink lesions with better identification of malignant neoplasms and ultimately will improve patient experience and reduce skin cancer morbidity and, hopefully, mortality. In conclusion, from a purely selfish dermatologists’ perspective, embracing new imaging technologies for diagnosing and managing neoplastic and inflammatory skin diseases is necessary in order to be at the forefront of the exciting technology revolution in medicine in the 21st century. In this spirit we commend Caterina Longo and colleagues for their insightful review.
Conflicts of interest None declared. 1
San Gallicano Dermatological Institute, IRCCS, IFO, Via Chianesi 53, 00144 Rome, Italy 2 Dermatology Research Centre, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia 3 Department of Dermatology, Princess Alexandra Hospital, Brisbane, QLD, Australia E-mail: [email protected] ORCID: M.A.: orcid.org/0000-00025772-4937; H.P.S.: orcid.org/00000002-4770-561X
M . A R D I G O 1 H.P. SOYER2,3
References 1 Soyer HP, Prow TW. Reflectance confocal microscopy in the diagnosis of nodular skin lesions. Br J Dermatol 2013; 169:4–5. 2 Giacomel J, Zalaudek I. Pink lesions. Dermatol Clin 2013; 31:649–78. 3 Guitera P, Menzies SW, Longo C et al. In vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a twostep method: analysis of 710 consecutive clinically equivocal cases. J Invest Dermatol 2012; 132:2386–94. 4 Braga JC, Scope A, Klaz I et al. The significance of reflectance confocal microscopy in the assessment of solitary pink skin lesions. J Am Acad Dermatol 2009; 61:230–41. 5 Longo C, Moscarella E, Argenziano G et al. Reflectance confocal microscopy in the diagnosis of solitary pink skin tumors: review of diagnostic clues. Br J Dermatol 2015; 173:31–41. 6 Zarbo RJ, Meier FA, Raab SS. Error detection in anatomic pathology. Arch Pathol Lab Med 2005; 129:1237–45.
© 2015 British Association of Dermatologists
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
