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Background: Topical photodynamic therapy (PDT) is widely used to treat superficial nonmelanoma skin cancer and dysplasia, and is generally well tolerated. However, as with all treatments, adverse effects may occur and awareness may facilitate approaches to prevention and management., Objectives: To review the available evidence relating to the adverse effects of topical PDT, to help inform recommendations in updated clinical guidelines produced by the British Association of Dermatologists and British Photodermatology Group, and the efficacy of preventative and therapeutic approaches., Methods: This review summarizes the published evidence related to the adverse effects of topical PDT and attempts to interpret this evidence in the context of patient risk and management., Results: Pain and discomfort during PDT are acute adverse effects, which can be minimized through the use of modified and low-irradiance PDT regimens and do not therefore usually limit successful treatment delivery. Other adverse effects include the risk of contact allergy to photosensitizer prodrugs, although this is rare but should be kept in mind, particularly for patients who have received multiple PDT treatments to larger areas. There are no other significant documented longer-term risks and, to date, no evidence of cumulative toxicity or photocarcinogenic risk., Conclusions: Topical PDT is usually well tolerated, reinforcing the utility of this important therapeutic option in dermatology practice. The main acute adverse effect of pain can typically be minimized through preventative approaches of modified PDT regimens. Other adverse effects are uncommon and generally do not limit treatment delivery., (© 2018 British Association of Dermatologists.)

Background: Topical photodynamic therapy (PDT) is an established treatment option for low-risk basal cell carcinoma (BCC)., Objectives: To compare efficacy, cosmesis and tolerability of PDT for BCC with alternative treatments., Methods: MEDLINE, PubMed, Embase and CENTRAL databases were searched from inception until 1 September 2017. Included studies were randomized controlled trials (RCTs) of PDT for nodular (n) and superficial (s) BCC reporting at least one of the following outcomes: clearance at 3 months and sustained at 1 or 5 years; recurrence at ≥ 1 year; cosmesis; adverse events; tolerability., Results: From 2331 search results, 15 RCTs (2327 patients; 3509 BCCs) were included. PDT efficacy (5-year sustained clearance) was high but inferior to excisional surgery [nBCC pooled risk ratio (RR) 0·76; 95% confidence interval (CI) 0·63-0·91], and without re-treatment of partially responding lesions, was modestly inferior to imiquimod (sBCC: RR 0·81; 95% CI 0·70-0·95) and similar to fluorouracil (sBCC: RR 0·88; 95% CI 0·75-1·04). Five-year sustained clearance was inferior with conventional vs. fractionated PDT (sBCC: RR 0·76; 95% CI 0·68-0·84). PDT cosmesis was superior to surgery (sBCC: RR 1·68, 95% CI 1·32-2·14; nBCC: RR 1·82, 95% CI 1·19-2·80) and cryosurgery (BCC: RR 3·73, 95% CI 1·96-7·07), and without re-treatment of partially responding lesions was similar to imiquimod (sBCC: RR 1·01, 95% CI 0·85-1·19) and fluorouracil (sBCC: RR 1·04, 95% CI 0·88-1·24). Peak pain was higher but of shorter duration with PDT than topical treatments. Serious adverse reactions were rarer with PDT than imiquimod (sBCC: RR 0·05, 95% CI 0·00-0·84) and fluorouracil (sBCC: RR 0·11, 95% CI 0·01-2·04). Combination PDT regimens demonstrated reduced recurrence and improved cosmesis; however, results from these small studies were often nonsignificant., Conclusions: PDT is an effective treatment for low-risk BCC, with excellent cosmesis and safety. Imiquimod has higher efficacy than single-cycle PDT but more adverse effects. Highest efficacy is with excisional surgery. Fractionated and combination PDT options warrant further study., (© 2018 British Association of Dermatologists.)

For squamous cell carcinoma (SCC) treated using Mohs micrographic surgery (MMS), interpretation of haematoxylin and eosin-stained frozen sections can be challenging. In these situations, ancillary use of immunostaining is a useful tool for the Mohs surgeon. However, use of immunostaining in MMS laboratories is limited, mainly because current manual immunostaining platforms are subject to operator error, and automated immunostaining, albeit accurate, is too slow for inclusion in MMS. In this report, we describe a novel 1-hour protocol for rapid frozen section immunocytochemistry, using the pancytokeratin markers AE1/AE3. This protocol has been specifically designed to integrate the speed of manual techniques and the accuracy of automated platforms, making it a valuable addition to the MMS laboratory. We propose that in selected or histologically challenging cases, there is a role for the use of this novel protocol, allowing the Mohs surgeon to more confidently declare tumour clearance, thus preventing further unnecessary surgery and preserving healthy tissue., (© 2018 British Association of Dermatologists.)

Trichoepitheliomas are benign cutaneous tumours often occurring on the face and can lead to considerable psychological distress to its sufferers. Treatment is often difficult, and surgery is limited by the obvious scars and multiple numbers of lesions. Carbon dioxide laser ablation can be used safely with good cosmetic outcome and low recurrence rate, and in this article, we describe our experience in the treatment of these tumours with the carbon dioxide laser. This is the largest reported series in the literature.

Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.

Angiofibromas are one of the dermatological hallmarks of tuberous sclerosis. Various ablative treatments have been trialled and more recently topical rapamycin has been proposed. We present our experience of treatment of angiofibromas using carbon dioxide (CO 2 ) laser ablation and provide a timely literature review. Nine patients were retrospectively identified as being treated with CO 2 laser between 2009 and 2015. Three patients were male, six were female, median age at first treatment was 28 (range 15-49) years and the median number of treatments was two (range 1-17). Four of these patients could be contacted for a post-treatment telephone interview. All reported an improvement in appearance of angiofibromas following treatment and that they would recommend CO 2 laser ablation to others. Three of the four reported recurrence of some lesions following treatment. The only side effect reported by one patient was transient hyperpigmentation. CO 2 laser ablation appears to be a well-tolerated, efficacious treatment for angiofibromas with few long-term side effects.

Becker's naevus is a hamartoma that often appears during puberty. Clinically this presents with a pigmented and often hairy patch most often on the shoulders. Treatment has always been challenging and lasers are often used with mixed results. This article reviews the evidence of all the laser treatments used in Becker's naevus and analyses the findings from the published studies and trials.

Background: The current recommended treatment for lentigo maligna (LM) is surgical resection, which can cause significant scarring. The reported recurrence rate after Mohs micrographic surgery is 0-6·25%. There is little published data on long-term outcome after imiquimod therapy. Several reports record progression to LM melanoma during treatment. Clinical assessment of clearance is difficult. Histological confirmation is preferred but risks sampling error and missing areas of invasion. Confocal microscopy can be used to assess entire lesions., Objectives: To assess the 5-year recurrence rate of LM after imiquimod treatment., Methods: Forty patients with LM were treated with imiquimod between 2002 and 2007. Their previous treatments included cryotherapy, incomplete surgical excision and radiotherapy. All applied imiquimod three times per week for 6 weeks; 25 (62·5%) experienced inflammation. The other 15 (37·5%) then applied imiquimod five times per week for a further 4 weeks; all experienced inflammation. All patients were subsequently examined and biopsied. Clinical clearance did not always correlate with histological clearance. Eleven patients (27·5%) had residual LM on histology and underwent surgical excision. At the time of this study, three patients had died (deaths were unrelated to LM). Eighteen of the 27 patients (66·7%) who were clear on biopsy after imiquimod attended for the study and were assessed using confocal microscopy (Vivascope 1500 and 3000)., Results: The recurrence rate of LM in patients who were clear on histology after imiquimod treatment who attended for this follow-up study was 0% (n = 18)., Conclusions: Imiquimod is an effective long-term treatment for LM. Its use avoids potentially disfiguring surgical resection., (© 2015 British Association of Dermatologists.)

Optical coherence tomography (OCT) has been shown to be of clinical value in imaging basal cell carcinoma (BCC). A novel dual OCT-video imaging system, providing automated registration of OCT and dermoscopy, has been developed to assess the potential of OCT in measuring the degree of sub-clinical spread of BCC. Seventeen patients selected for Mohs micrographic surgery (MMS) for BCC were recruited to the study. The extent of BCC infiltration beyond a segment of the clinically assessed pre-surgical border was evaluated using OCT. Sufficiently accurate (<0.5 mm) registration of OCT and dermoscopy images was achieved in 9 patients. The location of the OCT-assessed BCC border was also compared with that of the final surgical defect. Infiltration of BCC across the clinical border ranged from 0 mm to >2.5 mm. In addition, the OCT border lay between 0.5 mm and 2.0 mm inside the final MMS defect in those cases where this could be assessed. In one case, where the final MMS defect was over 17 mm from the clinical border, OCT showed >2.5 mm infiltration across the clinical border at the FOV limit. These results provide evidence that OCT allows more accurate assessment of sub-clinical spread of BCC than clinical observation alone. Such a capability may have clinical value in reducing the number of surgical stages in MMS for BCC. There may also be a role for OCT in aiding the selection of patients most suitable for MMS.

Background: Mohs micrographic surgery (MMS) is the preferred treatment modality for high-risk nonmelanoma skin cancer because of the high cure rates and tissue-sparing effect. Its outcome is highly dependent on the expertise and accuracy of the Mohs surgeon in the interpretation of frozen sections., Objective: This retrospective study evaluated the level of concordance between Mohs surgeons and dermatopathologists in reading histology slides from MMS procedures., Methods and Materials: A Mohs surgeon read 170 randomly selected slides for a quality assurance audit during excision, and then a dermatopathologist blindly read them at a separate time. Absence or presence of tumour and the final diagnosis were recorded on a standardized form., Results: An overall concordance of 99.4% was demonstrated. True discordance was recorded in only one of 170 cases. Intraepidermal atypia was the most challenging scenario for Mohs surgeons., Conclusions: The high rate of agreement in this study confirms that adequately trained MMS surgeons have sufficient expertise and training for accurate and precise frozen sections interpretation., (© 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.)

Background: Mohs micrographic surgery offers high cure rates of nonmelanoma skin cancers with optimal sparing of normal tissue. However, it is generally more time-consuming and labour-intensive than traditional surgery. Optical coherence tomography (OCT) is an emergent technology that has the potential to diagnose basal cell carcinoma (BCC) in vivo., Objective: To compare the efficiency and accuracy of ex vivo OCT with frozen-section histology for identifying BCC in Mohs surgery., Methods: Thirty-eight patients were enrolled. After the stages were taken, images were captured with an OCT microscope and subsequently processed for standard frozen sections., Results: In total, 75 sections were scanned and the mean time to produce one OCT image was 7 min. In four of 26 positive haematoxylin-eosin sections and 23 of 49 negative sections, there was a good correlation with OCT images. The sensitivity and specificity were 19% and 56%, respectively., Conclusions: It is possible to identify BCC with ex vivo OCT and this is more rapidly obtained than with haematoxylin-eosin frozen sections. However, tumour visualization in OCT was disappointing. Practical benefit may be obtained by optimizing this technology and combining it with other new diagnostic tools., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Background: Dermatofibrosarcoma protuberans (DFSP) has conventionally been treated with wide local excision. More recently Mohs micrographic surgery (MMS) has been advocated., Objectives: To assess our departmental experience with DFSP in the context of a literature review relating to DFSP treated with MMS., Methods: This was a case review of 35 patients with DFSP treated between 1998 and 2009 with MMS using paraffin-embedded sections., Results: Seventeen patients required one horizontal layer to clear their tumour, 10 patients needed two and eight patients needed three layers or more. The median preoperative clinical size was 6 cm(2) (range 0·75-54·8) and the median postoperative wound size was 46·8 cm(2) (range 4-145·2). Tumour persistence has not been observed in any of our patients after a median follow-up duration of 29·5 months (range 6-146)., Conclusions: We present 35 DFSP patients, none of whom showed persistent tumour after treatment with 'slow' MMS using paraffin sections. We advocate MMS as the treatment of choice for DFSP, especially for tumours over the head and neck region where tissue conservation is particularly important., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Gastrointestinal stromal tumors (GISTs) rarely metastasize to the skin. We describe 5 patients with GIST with subcutaneous and cutaneous metastases. The mean age at metastasis was 54 years (range 30-68 years) with a male predominance (4:1). Primary tumors occurred in the stomach (n = 3), small bowel (n = 1), and abdomen, not otherwise specified (n = 1). The average time from primary tumor resection to the resection of skin metastases was 59 months (range 11-155 months). The metastases occurred in the scalp (n = 2), cheek (n = 1), and abdomen (n = 2) with 3 patients presenting with solitary nodules and 2 patients with multiple nodules. The average size was 2 cm (range 0.6-4 cm). Histologically, 2 cases were spindled and 3 cases demonstrated mixed epithelioid and spindle cell morphology. All were confirmed to have CD117 reactivity. KIT genotyping was performed in 4 of 5 cases. Two cases harbored a mutation in exon 11, and the remaining 2 cases were wild type in exons 9, 11, 13, and 17. All 5 patients had multiple concurrent or subsequent abdominal and/or hepatic metastases. In 4 patients with an average follow-up of 32 months (range 6-75 months), after the resection of the metastases, 2 were alive with disease and 2 died of disease. Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient.

Background: Distinguishing sun-induced melanocyte atypia from residual melanoma in situ (MIS) can be challenging, particularly when working with frozen sections. Immunostains such as melanoma-associated antigen recognized by T cells (MART-1) can assist, but paraffin sections provide an optimal means of analyzing melanocyte morphology., Objective: To verify the effectiveness of a 2-hour paraffin processing technique that uses microwave technology in the preparation of MIS sections., Methods: Twelve MIS debulk specimens were divided into 4 pieces with each piece processed 1 of 4 ways: our 2-hour paraffin technique with hematoxylin and eosin (H&E), conventional 24-hour paraffin processing with H&E, frozen sections with H&E, and frozen sections with MART-1 immunostaining. A Mohs surgeon and a dermatopathologist compared all specimens in a blinded fashion using a 3-point ranking scale to assess ease of visualizing normal melanocytes, ease of visualizing abnormal melanocytes, and overall ability to adequately visualize epidermal and dermal structures., Results: A nonparametric signed rank test indicated no significant differences between our microwave technique and conventional paraffin processing in all 3 criteria (p=.29, .63, .75, respectively). Our microwave technique was significantly better than frozen H&E sections for all 3 criteria (p=.046, .004, .005, respectively)., Conclusion: This rapid microwave tissue processing technique is comparable with conventional paraffin section processing.

Non-Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive genodermatosis characterized by skin fragility and blistering. It is usually caused by mutations in the genes encoding the basement membrane proteins laminin 5 or type XVII collagen. Clinically, impaired wound healing and chronic erosions cause major morbidity in affected patients. Previously it was thought that these individuals, unlike patients with dystrophic EB, did not have an increased risk of developing skin cancer. However, we describe three patients with non-Herlitz JEB (aged 42, 56 and 75 years) who developed cutaneous squamous cell carcinomas (SCCs). The tumours were well-differentiated in two cases, but one patient had multiple primary SCCs that were either well- or moderately differentiated. Most cases of SCC in non-Herlitz JEB described have occurred in those with laminin 5 defects and on the lower limbs. These clinicopathological observations have important implications for the management of patients with this mechanobullous disorder as well as providing further insight into the biology of skin cancer associated with chronic inflammation and scarring., (Copyright 2004 European Academy of Dermatology and Venereology)

Background: Cutaneous squamous cell carcinoma (SCC) is particularly problematic in certain patient groups, including patients with dystrophic or junctional epidermolysis bullosa (DEB/JEB). Theoretically, vaccination against a cell surface antigen which is expressed on this type of tumour could prevent SCC development, as well as treat primary and metastatic disease in this patient group. Preliminary studies have suggested that MUC1, a transmembrane glycoprotein, is overexpressed in sporadic cutaneous SCCs, and MUC1 has been used with some success as a target antigen for vaccine development in breast cancer, where it is expressed on > 50% of neoplastic cells in approximately 50-80% of tumours. Furthermore, aberrant glycosylation of MUC1 has been detected in this and other cancer types; however, the glycosylation status of MUC1 in cutaneous SCC is not known., Objectives: To investigate the expression and glycosylation status of MUC1 in SCCs arising in patients with DEB and JEB, and for comparison in sporadic SCCs and sporadic Bowen's disease., Methods: Immunohistochemical analysis of MUC1 in 30 SCCs from subjects with DEB/JEB, 55 sporadic SCCs and 30 sporadic lesions of Bowen's disease was carried out using four separate monoclonal antibodies which recognize different isoforms of MUC1., Results: Expression of MUC1 was detected in 100% of SCCs arising in patients with DEB and JEB; > 50% of neoplastic cells stained positive for MUC1 in 57% of DEB/JEB SCCs, with over 95% of tumour cells immunopositive in 33% of cases. MUC1 expression was also observed in 95% of sporadic SCCs and 97% of Bowen's disease, with 36% of sporadic SCCs immunopositive for MUC1 in > 50% of tumour cells. Investigation of the glycosylation status showed that MUC1 was predominantly hyperglycosylated in the DEB/JEB and sporadic tumours., Conclusions: The results demonstrate that a significant proportion of DEB/JEB and sporadic SCCs express MUC1 in > 50% of tumour cells. Therefore, MUC1 may be a suitable candidate antigen against which to develop a tumour vaccine for these patient groups.

Squamous cell carcinoma (SCC) is a common complication in individuals with recessive dystrophic epidermolysis bullosa (RDEB). For the severe Hallopeau-Siemens subtype, the mortality rate from SCC is over 55% by the age of 40 y. Currently, little is known about the molecular pathology or cell biology of SCC in RDEB. In this study, we compared gene expression in RDEB SCC (n=3) and non-EB SCC (n=3) with corresponding RDEB and non-EB peri-tumoral skin, with microarray analysis using DermArray membranes as well as semi-quantitative and real-time RT-PCR. Both tumor sets showed downregulation of epidermal differentiation markers (e.g., profilaggrin, keratins 1 and 10) as well as certain pro-apoptotic genes (e.g., death-associated kinase-3 or ZIP kinase). Likewise, in both groups there was upregulation of matrix metalloproteinase 1 and laminin 5 in the tumors. But we found that the expression of insulin-like growth factor-binding protein-3 (IGFBP-3) was lower (mean of 5.8-fold) in RDEB SCC compared with non-EB SCC. These data were verified by immunohistochemistry. IGFBP-3 has an important role in cancer cell apoptosis mediated via the nuclear retinoid X receptor alpha (RXRalpha). Reduced expression of IGFBP-3 in RDEB SCC may provide a partial explanation for the aggressive behavior and poor prognosis of these tumors in this genodermatosis.

Epidermolysis bullosa (EB) encompasses a group of inherited blistering skin disorders classified into three main subtypes of simplex, junctional and dystrophic. In recent years there have been substantial advances in our understanding of the molecular basis of these conditions and in the management of such patients. In spite of this progress, squamous cell carcinoma (SCC) is still a major cause of morbidity and mortality, particularly in Hallopeau--Siemens recessive dystrophic EB. The reason why dystrophic EB patients readily develop SCC with such a poor prognosis remains a mystery. This article reviews the epidemiology of cancer in inherited EB and also discusses the clinical features, histological assessment and treatment options of SCC in EB.