Defining the actinic keratosis field: a literature review and discussion.

Despite the chronic and increasingly prevalent nature of actinic keratosis (AK) and existing evidence supporting assessment of the entire cancerization field during clinical management, a standardized definition of the AK field to aid in the understanding and characterization of the disease is lacking. The objective of this review was to present and appraise the available evidence describing the AK cancerization field, with the aim of determining a precise definition of the AK field in terms of its molecular (including genetic and immunological), histological and clinical characteristics. Eight European dermatologists collaborated to conduct a review and expert appraisal of articles detailing the characteristics of the AK field. Articles published in English before August 2016 were identified using PubMed and independently selected for further assessment according to predefined preliminary inclusion and exclusion criteria. In addition, a retrospective audit of patients with AK was performed to define the AK field in clinical terms. A total of 32 review articles and 47 original research articles provided evidence of sun-induced molecular (including genetic and immunological) and histological skin changes in the sun-exposed area affected by AK. However, the available literature was deemed insufficient to inform a clinical definition of the AK field. During the retrospective audit, visible signs of sun damage in 40 patients with AK were assessed. Telangiectasia, atrophy and pigmentation disorders emerged as 'reliable or very reliable' indicators of AK field based on expert opinion, whereas 'sand paper' was deemed a 'moderately reliable' indicator. This literature review has revealed a significant gap of evidence to inform a clinical definition of the AK field. Therefore, the authors instead propose a clinical definition of field cancerization based on the identification of visible signs of sun damage that are reliable indicators of field cancerization based on expert opinion.

The importance of patient-centred care to overcome barriers in the management of actinic keratosis.

Visible actinic keratosis (AK) lesions and subclinical (non-visible) sun damage in the field of cancerization are associated with risk of both non-melanoma skin cancer, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), and, more rarely, melanoma. As the incidences of AK and skin cancer are increasing, effective prevention and treatment of AK is essential to minimize disease burden and improve patient quality of life. Currently, AK lesions are often left untreated and field therapies are underused. Patient-centred care, with a focus on the patient-physician relationship, has proven cost-effective, and improved clinical outcomes and patient satisfaction in a number of therapy areas. Strategies for applying patient-centred care to AK are warranted. Existing barriers to the effective treatment of AK were identified and patient-centric strategies to overcome each barrier were discussed. Barriers to effective AK treatment include poor disease awareness (for both patient and physician), concerns associated with the cosmetic effects of treatment, treatment-related side effects, cost perceptions for lesion-directed vs field-directed therapies, and inadequate adherence, particularly with long treatment duration. Overcoming these barriers will involve patient and physician education that promotes: disease prevention and awareness; the importance of self-examination; an understanding of treatment options; and the importance of adherence to treatment. To maximize its effectiveness, education should be delivered within a patient-centric framework, where the relationship between patient and physician is built on effective communication, empathy and a feeling of partnership. Patient-centric care, including patient education, is key to overcoming the barriers associated with effective AK treatment.

Acantholytic dermatosis of the vagina: the diagnostic challenge of acantholytic disease in the genital region.

We report the case of a 24-year-old woman with an 8-month history of deep pelvic pain and postcoital bleeding. Examination revealed desquamation of the vaginal epithelium with tender fissured plaques in the vagina, initially thought to be vaginal intraepithelial neoplasia. Histology showed squamous mucosa with suprabasal acantholysis and hyperkeratosis, and no evidence of viral infection, dysplasia or malignancy. These findings were consistent with acantholytic dermatosis (AD), a rare lesion that resembles Hailey-Hailey and Darier disease histopathologically, but can be distinguished on a clinical basis. Vulval cases of AD are well recognized, but to our knowledge, this is the first reported case involving the vaginal epithelium alone.

Linear porokeratosis with multiple squamous cell carcinomas successfully treated by electrochemotherapy.

Porokeratosis is a clonal epidermal disorder of keratinization characterized by annular lesions with an atrophic centre and a hyperkeratotic edge. The cornoid lamella is the histopathological hallmark. Six clinical variants are recognized: porokeratosis of Mibelli; disseminated superficial porokeratosis; disseminated superficial actinic porokeratosis (DSAP); porokeratosis plantaris et palmaris disseminata; punctate porokeratosis and linear porokeratosis. Linear porokeratosis is the type most frequently associated with malignant transformation into squamous cell carcinoma (SCC). It is thought to represent a mosaic form of DSAP and has an incidence of less than 1 in 200 000; treatment options are limited. We describe a patient with systematized linear porokeratosis and multiple SCCs who was successfully treated with bleomycin electrochemotherapy (ECT), a form of intralesional chemotherapy. In view of their large number, the individual SCCs were treated with bleomycin ECT. One year post-treatment the patient remains tumour free. To our knowledge, this is the first case of multiple SCCs treated by ECT in the context of systematized linear porokeratosis. Our case highlights the challenges associated with diagnosing and managing this unusual form of porokeratosis.

Suppression of TGFß and Angiogenesis by Type VII Collagen in Cutaneous SCC.

BACKGROUND: Individuals with severe generalized recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disorder caused by mutations in the COL7A1 gene, develop unexplained aggressive squamous cell carcinomas (SCC). Here we report that loss of type VII collagen (Col7) in SCC results in increased TGFß signaling and angiogenesis in vitro and in vivo. METHODS: Stable knockdown (KD) of Col7 was established using shRNA, and cells were used in a mouse xenograft model. Angiogenesis was assessed by immunohistochemistry, endothelial tube-forming assays, and proteome arrays. Mouse and zebrafish models were used to examine the effect of recombinant Col7 on angiogenesis. Findings were confirmed in anonymized, archival human tissue: RDEB SCC tumors, non-EB SCC tumors, RDEB skin, normal skin; and two human RDEB SCC cell lines. The TGFß pathway was examined using immunoblotting, immunohistochemistry, biochemical inhibition, and siRNA. All statistical tests were two-sided. RESULTS: Increased numbers of cross-cut blood vessels were observed in Col7 KD compared with control xenografts (n = 4 to 7 per group) and in RDEB tumors (n = 21) compared with sporadic SCC (n = 24, P < .001). Recombinant human Col7 reversed the increased SCC angiogenesis in Col7 KD xenografts in vivo (n = 7 per group, P = .04). Blocking the interaction between α2ß1 integrin and Col7 increased TGFB1 mRNA expression 1.8-fold and p-Smad2 levels two-fold. Increased TGFß signaling and VEGF expression were observed in Col7 KD xenografts (n = 4) compared with control (n = 4) and RDEB tumors (TGFß markers, n = 6; VEGF, n = 17) compared with sporadic SCC (TGFß markers, n = 6; VEGF, n = 21). Inhibition of TGFß receptor signaling using siRNA resulted in decreased endothelial cell tube formation (n = 9 per group, mean tubes per well siC = 63.6, SD = 17.1; mean tubes per well siTßRII = 29.7, SD = 6.1, P = .02). CONCLUSIONS: Type VII collagen suppresses TGFß signaling and angiogenesis in cutaneous SCC. Patients with RDEB SCC may benefit from anti-angiogenic therapy.

Physician perceptions and experience of current treatment in actinic keratosis.

BACKGROUND: Topical therapy is important in the treatment of actinic keratosis (AK), a major risk factor for, and early development stage of, squamous cell carcinoma. Despite this, research addressing the limitations and challenges associated with topical field therapy in actinic keratosis is lacking. OBJECTIVES: The aim of this study was to highlight the challenges associated with maximizing compliance in patients receiving topical AK therapy and to investigate real-world experience with currently available topical therapies including perceptions of adherence and persistence. METHODS: A 45-min online survey was developed and completed by physicians in eight countries. All had previously prescribed topical AK therapy and ≥1 other treatment. Physicians' consensus was summarized as overall agreement/disagreement from ≥70% of respondents (≥60% for case-specific questions). RESULTS: More than 70% of the 427 respondents agreed that topical field therapy is essential and had concerns that lengthy treatments and local skin reactions caused non-adherence/persistence. More than 90% of physicians would preferentially prescribe the shortest duration treatment to such patients. CONCLUSIONS: The research clarifies the challenges associated with prescribing topical AK therapy and highlights that short treatment duration and rapid clearance of skin reactions are key considerations for physicians. This provides a basis for the generation of recommendations for improving the real-world efficacy of topical therapy.

Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling. METHODS: We combined laser capture microdissection with the Affymetrix HGU133 Plus 2.0 microarrays to profile 30 cSCC and 10 AKs. RESULTS: We identified a core set of 196 genes that are differentially expressed between AK and cSCC, and are enriched for processes including epidermal differentiation, cell migration, cell-cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the mitogen activated protein kinase (MAPK) pathway in cSCC compared with AK. Furthermore, the histological subtype of the tumour was shown to influence the expression profile. CONCLUSION: These data indicate that the MAPK pathway may be pivotal to the transition from AK to cSCC, thus representing a potential target for cSCC prevention. In addition, transcriptome differences identified between cSCC subtypes have important implications for future development of targeted therapies for this malignancy.

Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study).

BACKGROUND: Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown. OBJECTIVES: To compare three PsA screening questionnaires in a head-to-head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard. METHODS: This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria. RESULTS: In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis. CONCLUSION: Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.

A surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population.

Skin cancer is a frequent complication of organ transplantation. Current guidelines advise specialist skin surveillance but there are limited data on how these should be implemented. This study determines overall burden of cancer and relevant intervals for strategic surveillance in an ethnically diverse transplant population. Prospective data on time to first and subsequent cancers and cumulative burden with respect to defined risk factors were analyzed in a cohort of 1010 patients in a UK center over 22 years. Among 931 individuals transplanted >6 months (mean 10.3 years), 1820 skin cancers occurred in 267 (29%) individuals and were multiple in 66%. Cumulative incidence at 5, 10, 20 and 30 years was 11%, 25%, 54% and 74%, with median time to second, third and fourth cancers of 24, 14.7 and 8.4 months, respectively. Tumors were overwhelmingly squamous and basal cell carcinomas (73% and 24%, respectively). Skin phototype, ultraviolet radiation exposure, age at transplant and duration of transplant were significant risk predictors and were used to construct clinically relevant surveillance intervals. This study provides a comprehensive, prospective analysis of skin cancer morbidity and risk in an ethnically diverse transplant population from which we derive an evidence-based skin cancer surveillance program.

Synchronous melanoma and renal carcinoma: a clinicopathological study of five cases.

An increased frequency of renal carcinoma in men with melanoma has been reported in population based-studies. We report the clinicopathological findings of five cases of synchronous renal cell carcinoma (RCC), identified after routine radiological staging for cutaneous malignant melanoma (MM) between October 2006 and October 2008. The five patients (three men and two women, with a mean age of 62.4 years), presented with six melanomas of varying subtypes. The mean Breslow thickness was 1.87 mm. There was no family history of cancer in any of the cases. Routine radiological staging identified a mass arising from the left kidney in three cases and the right kidney in two cases. All patients underwent radical nephrectomy, and histology in each case confirmed RCC of the clear-cell subtype. Mean follow-up was 3 years. Although the simultaneous occurrence of RCC and MM may be coincidental, there are several plausible aetiological links. Further analysis of the synchronous occurrence of MM and renal cancer may provide therapeutic insights into these two important tumours.

Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis.

Tumours lacking argininosuccinate synthetase-1 (ASS1) are auxotrophic for arginine and sensitive to amino-acid deprivation. Here, we investigated the role of ASS1 as a biomarker of response to the arginine-lowering agent, pegylated arginine deiminase (ADI-PEG20), in lymphoid malignancies. Although ASS1 protein was largely undetectable in normal and malignant lymphoid tissues, frequent hypermethylation of the ASS1 promoter was observed specifically in the latter. A good correlation was observed between ASS1 methylation, low ASS1 mRNA, absence of ASS1 protein expression and sensitivity to ADI-PEG20 in malignant lymphoid cell lines. We confirmed that the demethylating agent 5-Aza-dC reactivated ASS1 expression and rescued lymphoma cell lines from ADI-PEG20 cytotoxicity. ASS1-methylated cell lines exhibited autophagy and caspase-dependent apoptosis following treatment with ADI-PEG20. In addition, the autophagy inhibitor chloroquine triggered an accumulation of light chain 3-II protein and potentiated the apoptotic effect of ADI-PEG20 in malignant lymphoid cells and patient-derived tumour cells. Finally, a patient with an ASS1-methylated cutaneous T-cell lymphoma responded to compassionate-use ADI-PEG20. In summary, ASS1 promoter methylation contributes to arginine auxotrophy and represents a novel biomarker for evaluating the efficacy of arginine deprivation in patients with lymphoma.

An unusual case of vulval papulonecrotic tuberculid.

The tuberculids are a group of rare cutaneous hypersensitivity reactions that occur in response to a distant focus of mycobacterial infection. Typically, Mantoux testing is strongly reactive, and clinical response to antituberculous treatment is rapid. The papulonecrotic subtype is one such clinical variant, consisting of multiple symmetrical papules, often with central necrosis, distributed preferentially over the trunk and limbs. Localized forms are rare, and mainly involve the genitalia in men. We describe a 26-year-old Indian woman with lymphatic and pulmonary tuberculosis (TB) in association with localized papulonecrotic tuberculid of the vulva, which resolved promptly on treating the underlying TB.

Expression of DNA mismatch repair proteins and MSH2 polymorphisms in nonmelanoma skin cancers of organ transplant recipients.

BACKGROUND: Organ transplant recipients (OTRs) have an increased risk of skin cancer. Treatment with azathioprine, commonly used in post-transplant immunosuppressive regimens, results in incorporation of 6-thioguanine (6-TG) into DNA. Mismatch repair (MMR)-defective cells are resistant to killing by 6-TG. Azathioprine exposure confers a survival advantage on MMR-defective cells, which are hypermutable and may therefore contribute to azathioprine-related nonmelanoma skin cancer, a phenomenon we have previously demonstrated in transplant-associated sebaceous carcinomas. The MSH2 protein is an important component of DNA MMR. The -6 exon 13 T>C MSH2 polymorphism is associated with impaired MMR, drug resistance and certain cancers. OBJECTIVES: To investigate (i) whether loss of MMR protein expression and microsatellite instability are over-represented in squamous cell carcinomas (SCCs) from OTRs on azathioprine compared with SCCs from immunocompetent patients, and (ii) whether the MSH2 -6 exon 13 polymorphism is over-represented in OTRs with skin cancer on azathioprine. METHODS: (i) Immunohistochemical staining was used to assess expression of the MMR proteins MSH2 and MLH1 in cutaneous SCCs from OTRs on azathioprine and from immunocompetent patients. (ii) Blood samples from OTRs on azathioprine with and without skin cancer were genotyped for the -6 exon 13 MSH2 polymorphism. RESULTS: (i) MSH2 and MLH1 protein expression was not altered in SCCs from OTRs on azathioprine and there was no difference in expression between SCCs from OTRs and immunocompetent patients. (ii) There was no association between MSH2 polymorphism genotype frequency and OTR skin cancer status. CONCLUSIONS: Despite previous findings in transplant-associated sebaceous carcinomas, defective MMR and the -6 exon 13 MSH2 polymorphism are unlikely to play a significant role in the development of SCC in OTRs on azathioprine.

Solasodine glycoalkaloids: a novel topical therapy for basal cell carcinoma. A double-blind, randomized, placebo-controlled, parallel group, multicenter study.

OBJECTIVE: To assess the safety and efficacy of a 0.005% mixture of solasodine glycosides (Zycure) in the treatment of basal cell carcinoma. Design Double-blind, randomized, and vehicle-controlled, parallel group study. SETTING: Ten centers in the United Kingdom. Participants Male, n = 50; female, n = 44; age range, 32-95 years (Table 1). INTERVENTION: Ninety-four patients were randomized on a 2 : 1 ratio (n = 62, Zycure; n = 32, vehicle). Histologically confirmed lesions were treated double blinded, twice daily under occlusion with Zycure or vehicle for 8 weeks. Patients were reviewed fortnightly for adverse effects and overall response. Successfully treated patients were followed up at six-month intervals for a year. MAIN OUTCOME MEASURES: The primary efficacy endpoint was histologically confirmed clearance of the basal cell carcinoma (2-mm punch biopsy) at the end of 8-week treatment. RESULTS: Efficacy (intention-to-treat population) at 8 weeks was 66% (41/62) in the Zycure group, compared to 25% (8/32) in the vehicle group (P < 0.001; Cochran-Mantel-Haenszel test). Ninety percent (37/41) of the Zycure group completed follow-up at six-month intervals for 1 year, of whom 78% (29/37) had no recurrence. There were no major treatment-related adverse effects, although 10 patients in Zycure group did not complete the treatment protocol for various reasons. CONCLUSION: We conclude that the solasodine glycoside cream Zycure is a safe therapy for basal cell carcinoma, with a cure rate of 66% at 8 weeks and 78% at 1 year follow-up.