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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.

Objective: Several questionnaires have been developed to screen for psoriatic arthritis (PsA) but head to head studies have found limitations. This study aimed to develop new questionnaires encompassing the most discriminative questions from existing instruments. Methods: Data from the CONTEST study, a head to head comparison of three existing questionnaires, were used to identify items with a Youden's index of ?0.1. These were combined using four approaches: CONTEST- simple additions of questions; CONTESTw- weighting using logistic regression; CONTESTjt- addition of a joint manikin and CONTESTtree- additional questions identified by CART analysis. These candidate questionnaires were tested in independent datasets. Results: 12 individual questions with a Youden's index of ?0.1 were identified but 4 of these were excluded due to duplication and redundancy. Weighting for two of these questions, was included in CONTESTw. Receiver operating characteristic (ROC) curve analysis showed that involvement in six joint areas on the manikin was predictive of PsA for inclusion in CONTESTjt. CART analysis identified a further 5 questions for inclusion in CONTESTtree. CONTESTtree was not significant on ROC analysis and discarded. The other three were significant in all datasets, although CONTESTw was slightly inferior to the others in the validation datasets. Potential cut points for referral are discussed. Conclusion: Of four candidate questionnaires combining existing discriminatory items to identify psoriatic arthritis in people with psoriasis three were found to be significant on ROC analysis. Testing in independent datasets identifies two questionnaires: CONTEST and CONTESTjt that should be pursued for further prospective testing. � 2014 American College of Rheumatology.

Background To report our experience with sentinel lymph node biopsy for staging patients with conjunctival melanoma. Methods A prospective review of patients with conjunctival melanoma who underwent sentinel lymph node biopsy at St Bartholomew9s Hospital from May 2008 to May 2012. The selection criterion for sentinel node biopsy depended on the tumour thickness (≥2 mm) and location of the conjunctival melanoma. The main outcome measures were the incidence of sentinel lymph node positivity and the procedure-related complications. Results In 4 years, 26 out of 70 patients met the selection criteria for sentinel lymph node biopsy. 4 patients declined and 22 patients consented for the procedure. Technetium-99m failed to identify a sentinel lymph node in four of the 22 patients (18%). Of the remaining 18 patients, two were found to have subclinical micrometastasis in regional lymph nodes. Median follow-up was 20 months (range 6–36 months). No false-negative events were observed. Complications of the procedure included transient blue staining of the epibulbar surface in five patients and transient facial nerve palsy in one patient. Conclusions Sentinel lymph node biopsy is a safe procedure with minimal complications. It should be considered for the staging of conjunctival melanomas, especially melanomas in non-limbal location or conjunctival melanomas ≥2 mm thick.

Expression of Axl, a receptor tyrosine kinase, is increased in cutaneous squamous cell carcinoma (SCC). Examination of a series of cutaneous SCC tumors revealed positive phospho-Akt (P-Akt) staining accompanied by weak TUNEL staining in Axl-positive tumors, suggesting an anti-apoptotic role for Axl in SCC survival. The role of Axl in UV-induced apoptosis was investigated in a cutaneous SCC cell line using retroviral short hairpin RNA sequences enabling stable Axl knock-down. We show that, although Axl knock-down has no effect on cell proliferation, it sensitizes cells to UV-induced apoptosis through increased activation of the pro-apoptotic protein Bad, a change in the conformation of Bax and Bak, release of cytochrome c into the cytosol, and activation of caspases. These events are accompanied by faster Akt dephosphorylation in UV-treated Axl knock-down cells and correlate with the degree of Axl knock-down. Treatment with the pan-caspase inhibitor zVAD-fmk partially rescued cells from UV-induced apoptosis but did not affect Bid cleavage or cytochrome c release, suggesting that cells die via the mitochondrial-mediated pathway. Thus, Axl confers resistance of SCC cells to apoptosis and displays potential as a target for therapeutic intervention in cutaneous SCC.

Background Topical therapy is important in the treatment of actinic keratosis, but guidance for improving adherence/persistence during topical therapy is still lacking. Objectives To utilize expert consensus to generate a list of recommendations to improve real-world efficacy when prescribing topical therapy for actinic keratosis. Methods An expert panel of eight dermatologists was convened to generate recommendations based on facilitated discussion and consensus generation using a modified Delphi session. The recommendations were ratified with the expert panel. Results Facilitated discussion generated 31 issues within five themes, which were prioritized using expert voting. Consensus was achieved on the importance of short and simple treatment regimens for maximizing patient compliance, physician awareness of the progression of actinic keratosis to squamous cell carcinoma, provision of appropriate patient information, and the use of effective communication strategies to educate physicians about actinic keratosis. Based on these key findings, eight recommendations were generated. Conclusions The recommendations will assist physicians when prescribing topical actinic keratosis therapy. Further research should focus on the types of patient outcomes that are influenced by the characteristics of topical field therapy.

The incidence of malignant melanoma (MM) is continuing to rise, although childhood MM remains rare. We describe an 8-year-old Afro-Caribbean girl who developed a non pigmented lesion on the tip of her left thumb, which persisted despite treatment in primary care with cryotherapy. At biopsy she was found to have an acquired acral MM. She underwent amputation of the distal phalanx of her thumb, together with positive sentinel lymph node (SLN) biopsy and subsequent axillary lymph node clearance and adjuvant chemotherapy. MMs are very rare in this age and skin-type group, therefore requiring strict diagnostic criteria. These criteria include the distinction from MM mimics, especially Spitz tumours, and an appropriate use of staging techniques such as SLN biopsy to influence management.

Palisaded neutrophilic and granulomatous dermatitis is a rare, cutaneous disease, associated with systemic diseases including rheumatoid arthritis and systemic lupus erythematosus.

Normal human skin is remarkably resistant to infection from the large numbers of microorganisms that routinely colonize its surface. In addition to the role of skin as a mechanical barrier, it has long been recognized that skin and other epithelia can produce a range of anti-microbial chemicals that play an important part in eliminating potential cutaneous pathogens. Anti-microbial peptides are an important evolutionarily conserved innate host defense mechanism in many organisms. Human beta defensin-1 and -2 are cysteine-rich, cationic, low molecular weight anti-microbial peptides that have recently been shown to be expressed in epithelial tissues. In this study, we describe the characterization of human beta defensin-1 and -2 mRNA and peptide expression in normal human skin. Using reverse transcription-polymerase chain reaction we demonstrate that human beta defensin-1 is consistently expressed in skin samples from various body sites. Human beta defensin-2 demonstrates expression that is more variable and is more readily detectable in facial skin and foreskin compared with skin from abdomen and breast. In situ hybridization localizes the human beta defensin-1 and -2 transcripts to keratinocytes within interfollicular skin. Using specific antibodies, we have shown that human beta defensin-1 and -2 peptides are localized to the Malpighian layer of the epidermis and/or stratum corneum and that there are interindividual and site-specific differences in intensity of immunostaining and the pattern of peptide localization. The localization of human beta defensins to the outer layer of the skin is consistent with the hypothesis that human beta defensins play an essential part in cutaneous innate immunity.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with a high risk of skin cancer. This condition is characterized by an abnormal susceptibility to human papillomavirus genotypes from the genus beta. The cutaneous lesions of EV first appear in childhood and are highly polymorphic. Multiple squamous cell carcinomas (SCC) of the skin develop subsequently on sun-exposed sites in about half of the patients. Benign cutaneous lesions are associated with polymorphic lesions such as pityriasis versicolor-like (PV-like) macules, flat warts and red macules. EV is believed to be an autosomal recessive disease (reviewed in ref. [1]). Two susceptibility loci, EV1 and EV2, have been mapped with EV1 containing the characterized EVER1 and EVER2 genes [2]. In this report, we present a 22-year-old Turkish male and his 45-year-old mother with extensive seborrheic keratosis-like (SK-like) viral warts with no family history of EV. Initial facial lesions developed aged 8 years and disseminated with time. PV-like brown scaly macules resembling pityriasis versicolor were observed on the trunk and neck (Fig. 1b and d). The patients showed SK-like viral warts characterized by dark brown or black pigmented proliferative lesions with hyperkeratotic surfaces. Facial SK-like lesions were dark and plaque-like (Fig. 1a and d). All lesions disappeared following liquid nitrogen cryosurgery (Fig. 1c). Blood profile (son) including full blood count, erythrocyte sedimentation rate, C-reactive protein, liver and renal function tests, serum lipid and cholesterol level, levels of immunoglobulins, complement components and circulating immune complexes were normal. The patient showed no decrease in the number of CD8+ T-cells as described previously for EV [10]. The patient was HIV-negative. Fig. 1 (a) Hyperpigmented SK-like lesions on the boy's face and forehead. (b) Brown, scaly PV-like macules on the neck and trunk. (c) Successful treatment of SK-like lesions by cryosurgery. (d) Multiple brownish plaques and SK-like lesions on face, neck and ... Skin biopsies were taken from a SK-like wart and histopathologic evaluation of a warty lesion revealed hyperkeratosis and hypergranulosis with vacuolation and koiliocytes consistent with HPV infection. The lesion showed mild to moderate dysplasia in the epidermis (Fig. 2). The dermatopathological findings were pathognomic for EV. Fig. 2 Histology of SK-like viral wart from the boy (a and b) and his mother (c and d) showing typical EV changes. (a and c) 50-fold magnification; (b and d) 200-fold magnification. HPV DNA analysis was performed on a formalin-fixed, paraffin-embedded hyperkeratotic lesion from the face. The sample was tested positive for oncogenic HPV type 8 using a multiple nested degenerated PCR method with the capacity to detect a broad spectrum of cutaneous, alpha- and beta-HPV types [3]. No other HPV types were detected. Genetic analysis of the genes EVER1 and EVER2, two known genes to be associated with this disease, did not detect any loss of function mutations by sequencing the coding exons from genomic DNA with previously described primers [2]. We found only a non-synonymous single nucleotide polymorphism in the intron between exon 10 and exon 11 (cacctgccc[c/g]ctggggaggcag) of EVER1. This phenotype of EV, dominated by SK-like lesions, has previously been reported in a subset of African EV patients [4–6]. This is the first report of this EV phenotype in a Caucasian family. The diagnosis of EV is supported by the characteristic histology and the presence of the EV-associated HPV8. Both patients showed PV-like scaly macules in addition to the clinically dominant SK-like warts. To our knowledge, EVER mutations have previously been described in few reports [2,7–9], with only one publication reporting the lack of EVER mutation [10]. Our analysis shows also lack of EVER1 and EVER2 mutations and represents a distinct clinical and genetic variant of EV underlining the probable involvement of other genetic loci in the development of this disease.

Sir, In response to the report of Le Mire et al.1 on the incidence of malignant melanoma in Oxford renal transplant recipients (RTRs), we detail our experience of melanoma in a series of RTRs at Bart’s and the London NHS Trust. Although incidence rates in our population were similar to those documented in the Oxford study, metastatic disease was more common, and we suspect that RTRs with melanoma may have a worse prognosis than their immunocompetent counterparts, although larger, multicentre studies are now required to confirm this. A retrospective clinical and histological review of melanomas diagnosed in patients attending a dedicated RTR dermatology clinic between 1990 and 2005 was performed. All specimens were resectioned and were assessed by an experienced dermatopathologist (R.C.). In a total population of 861 RTRs with a follow-up period of 8557 patient-years, there were seven cases of de novo melanoma (five invasive and two in situ) in three men and four women. All diagnoses were made in the RTR dermatology clinic. Clinicopathological data are presented in Table 1 and are illustrated in Figure 1. All patients were on prednisolone and azathioprine, with or without ciclosporin. The mean age at diagnosis was older than in Oxford [57·7 years (range 44-68) vs. 41] and the mean time from transplantation was shorter [102 months (range 10-247) vs. 132]. All patients had skin types I-III (although 20% of our RTR cohort have skin type V or VI). None had a family history of melanoma or fulfilled criteria for atypical mole syndrome, although two patients had several atypical naevi. A high proportion of patients had a history of other invasive skin tumours (five of seven vs. four of 10 in Oxford); in all but one patient (patient 1) these tumours arose prior to the diagnosis of melanoma. Melanomas were more commonly located on the head and neck in our series, with four of seven tumours occurring at this site, in contrast to the Oxford tumours which all occurred at extracephalic sites. Ten of 12 tumours in the Oxford series were superficial spreading melanomas, whereas this subtype accounted for two of our seven cases. As in the Oxford series, Breslow thickness in the majority of cases (five of seven) was < 1 mm, and an inflammatory response was either minimal or absent in all melanomas, as has previously been documented.2 A contiguous pre-existing naevus was present in only one case, and, similarly, was detected in only a minority (three of 12) of the Oxford cases, in contrast to a previous proposal that over half of all transplant melanomas arise in pre-existing naevi.2 All melanomas in our series were treated by complete surgical excision; sentinel lymph node biopsy was not available at the time these tumours were diagnosed. In most cases immunosuppression was reduced, but not stopped. Fig 1 Clinical and histological examples of melanoma in renal transplant recipients. (a) Patient 6: lentigo maligna melanoma on right side of nose, Breslow thickness 0·4 mm. (b) Patient 2: lentigo maligna on cheek. (c) Photomicrograph of histology, ... Table 1 Clinicopathological data This series represents an elevated incidence of melanoma in our London RTR cohort: the rate in 2003 for the general population in North East Thames was 6·5 and 8·1 per 100 000 population for men and women, respectively, and we would therefore have expected approximately 0·9 cases of melanoma to have arisen in our cohort (in which 64% are male). If in situ tumours are included, these 7 cases represent an approximately 7·8-fold increased incidence compared with the general population. This is remarkably similar to the eightfold increased rate found in Oxford, and is of the same order as that reported by Moloney et al.3 who reported a 6·6-fold increase in males with melanoma in an Irish transplant population. These more recent studies report rates higher than previous estimates.4-6 Three patients in our series, but only one patient in Oxford, died from metastatic melanoma. Two deaths occurred in RTRs with melanomas exceeding 2 mm Breslow thickness. In accordance with American Joint Committee on Cancer staging, the predicted 5-year survival for patient 3 was 67% and that for patient 4 was 63%,7 yet both died within approximately 2 years. Even more unexpectedly, patient 6 developed metastases from a lentigo maligna melanoma of Breslow thickness 0·4 mm, for which the expected 5-year survival is 95% or greater. Our series of patients is too small to give statistical confirmation of a poorer prognosis in RTRs and previous studies have also not had sufficient power to examine this, although a compromised outcome from melanoma has similarly been observed in individuals with human immunodeficiency virus infection or AIDS.8 The incidence of melanoma is rising faster than for any other major cancer and will continue to do so over at least the next 30 years.9 In conjunction with the steadily improving long-term survival from organ transplantation, it is likely that post-transplant melanoma will emerge as an increasing clinical problem in coming years. Many important questions have yet to be answered in this respect: whether prognosis is, indeed, worse for post-transplant melanoma, whether more aggressive management strategies are therefore required, and how reduction in immunosuppression should be approached. Although consensus statements such as those recently reported in this Journal are a useful guideline to management of post-transplant skin cancer,10 a firmer evidence base is now required. This is a particular priority for management of post-transplant melanoma, and sufficient power to reach meaningful conclusions is only likely to be achieved in the context of a multicentre study. Such a study is currently being coordinated within the SCOPE network (Skin Care in Organ transplant Patients, Europe: http://www.scopnetwork.org) by our centre, and we invite clinicians who are interested in participating to contact us.

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.

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.

Clinical Findings A 68- year-old man presented with a skin thickening of the anterior neck started few months earlier. Upper respiratory and digestive tract had already been examined which proved normal. On clinical examination a hyper pigmented massively indurated leathery plaque was seen on the anterior and lateral aspect of the neck from the submandibular region down to the jugular fossae. The plaque was firm, well demarcated and measured 15 by 12 cm in diameter. It had a cobblestone like appearance with exaggerated folds, and was non painful. Patient complained of a mild discomfort while swallowing saliva of recent onset, but was otherwise asymptomatic. All his routine blood test was normal. The full skin examination was otherwise unremarkable. Our main differential diagnosis at that stage included a reactive process such as a sclerodermatous process, a neoplastic reaction or a lymph proliferative disease.

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.

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.

Low concordance in grading atypical (dysplastic) melanocytic nevi (AMN) has been reported, and no systematic evaluation is available. We studied 123 AMN with architectural and cytologic atypia (40 associated with atypical-mole syndrome), classified according to standard criteria by 3 independent observers. Histologic variables included junctional and dermal symmetry, lateral extension, cohesion and migration of epidermal melanocytes, maturation, regression, nuclear features, nuclear grade, melanin, inflammatory infiltrate location, and fibroplasia. AMN (43 junctional and 80 compound) were graded mild (31), moderate (61), and severe (31). AMN-severe correlated with 3 or more nuclear abnormalities (especially pleomorphism, heterogeneous chromatin, and prominent nucleolus) and absence of regression, mixed junctional pattern, and suprabasilar melanocytes on top of lentiginous hyperplasia. AMN-severe diagnostic accuracy was 99.5% using these criteria, but only the absence of nuclear pleomorphism differentiated AMN-mild from AMN-moderate. No architectural features distinguishing AMN-mild from AMN-moderate were selected as significant by the discriminant analysis. AMN from atypical-mole syndrome revealed subtle architectural differences, but none were statistically significant in the discriminant analysis. Histologic criteria can reliably distinguish AMN-severe but fail to differentiate AMN-mild from AMN-moderate. AMN from atypical-mole syndrome cannot be diagnosed using pathologic criteria alone.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically

Paraneoplastic acanthosis nigricans (P-AN) characteristically has a sudden onset, rapid progression, and extensive cutaneous involvement. The association between P-AN and internal malignancy is well established and the most common association is with adenocarcinoma of gastrointestinal origin. We present the case of an 81-year-old man with a 12-month history of anorexia, weight loss, and clinical evidence of extensive acanthosis nigricans. After exhaustive and repeated investigations a papillary thyroid carcinoma and a follicular adenoma were identified and he improved upon its resection. To our knowledge, P-AN in association with thyroid neoplasm has been reported on only one previous occasion.

Paraneoplastic acanthosis nigricans (P-AN) characteristically has a sudden onset, rapid progression, and extensive cutaneous involvement. The association between P-AN and internal malignancy is well established and the most common association is with adenocarcinoma of gastrointestinal origin. We present the case of an 81-year-old man with a 12-month history of anorexia, weight loss, and clinical evidence of extensive acanthosis nigricans. After exhaustive and repeated investigations a papillary thyroid carcinoma and a follicular adenoma were identified and he improved upon its resection. To our knowledge, P-AN in association with thyroid neoplasm has been reported on only one previous occasion.

Background: We tested the relevance of clinical information in the histopathologic evaluation of melanocytic skin neoplasm (MSN). Methods: Histopathologic specimens from 99 clinically atypical MSN were circulated among ten histopathologists; each case had clinical information available in a database with a five-step procedure (no information; age/sex/location; clinical diagnosis; clinical image; dermoscopic image); each step had a histopathologic diagnosis (D1 through D5); each diagnostic step had a level of diagnostic confidence (LDC) ranging from 1 (no diagnostic certainty) to 5 (absolute diagnostic certainty). The comparison of the LDC was employed with an analysis of variance (ANOVA) for repeated measures. Findings: In D1 (no information), 36/99 cases (36.3%) had unanimous diagnosis; in D5 (full information available), 51/99 cases (51.5%) had unanimous diagnosis (p for difference between proportions

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 TGF β 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 TGF β 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 α2β1 integrin and Col7 increased TGFB1 mRNA expression 1.8-fold and p-Smad2 levels two-fold. Increased TGF β signaling and VEGF expression were observed in Col7 KD xenografts (n = 4) compared with control (n = 4) and RDEB tumors (TGF β markers, n = 6; VEGF, n = 17) compared with sporadic SCC (TGF β markers, n = 6; VEGF, n = 21). Inhibition of TGF β 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 siT βRII = 29.7, SD = 6.1, P = .02). Conclusions: Type VII collagen suppresses TGF β signaling and angiogenesis in cutaneous SCC. Patients with RDEB SCC may benefit from anti-angiogenic therapy.

This is a case of a 42-year-old atopic man with severe atopic dermatitis and asthma who despite long-term immunosuppression was not well controlled. He had a very high IgE at 7897 Iu/mL prior to treatment. He underwent two therapeutic plasma exchanges (TPEs) through two peripheral lines in our outpatient department, which led to an absolute decrease of 44.1% and 37% in his plasma IgE for each exchange, and immediate sustained improvement in shortness of breath, and atopic dermatitis, and hence led to a vast improvement in his quality of life. TPE offers a new exciting adjunctive treatment option for severe atopic individuals, where it may provide a novel role to reduce health burden and improve clinical symptoms. Further studies need to be performed to establish an optimal protocol and potential maintenance with recently available targeted anti-IgE biologics.

Keywords: actinic keratoses; Bowen's disease; squamous cell carcinoma; tumour markers

Objective To evaluate the safety and efficacy of 5% imiquimod cream for cutaneous dysplasia in high-risk renal transplant recipients. Design A randomized, blinded, placebo-controlled study comparing treated with control skin. Setting A specialist organ transplant dermatology clinic. Patients Twenty-one high-risk patients with skin cancer with comparable areas of clinically atypical skin on dorsal hands or forearms. Interventions Imiquimod or placebo (randomly assigned) applied 3 times a week for 16 weeks to 1 dorsal hand or forearm, with 8 months of follow-up. At week 16, biopsy samples were collected from preassigned sites in the treatment and control areas and were examined for dysplasia. Main Outcome Measures The proportion of patients showing reduced numbers of viral and keratotic lesions and reduced histological severity of dysplasia in the treatment vs control areas at week 16, serum creatinine levels, and tumors developing in the study sites. Results Fourteen patients receiving imiquimod and 6 receiving placebo completed the study. Seven patients using imiquimod (1 taking placebo) had reduced skin atypia, 7 using imiquimod (none taking placebo) had reduced viral warts, and 5 using imiquimod (1 taking placebo) showed less dysplasia histologically. In 1 year, fewer squamous skin tumors arose in imiquimod-treated skin than in control areas. Renal function was not adversely affected. Conclusions Topical 5% imiquimod cream seems to be safe on skin areas up to 60 cm2 in renal transplant recipients. It may be effective in reducing cutaneous dysplasia and the frequency of squamous tumors developing in high-risk patients. Larger studies are required to confirm these results. Author Affiliations: Centre for Cutaneous Research and Department of Dermatology, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London (Drs Brown, Cerio, Harwood, and Proby and Ms Atkins), and Cancer Research UK Skin Tumour Laboratory (Drs Ghali, Harwood, and Proby), London, England.

Contact Dermatitis

Summary We report a case of Jessner's lymphocytic infiltrate of the skin in an 11-year-old boy. This benign lymphocytic infiltrate was originally described in 1953, and classically occurs in middle-aged men. Its occurrence in children appears to be very rare, and there are only two other case reports in the literature.

p63 is up-regulated in melanoma and prevents nuclear accumulation of p53., The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents.

Using monoclonal antibodies in immunofluorescence techniques, the subclass distribution of anti-basement membrane zone IgG antibodies was studied in the skin, placenta, and serum of patients with pemphigoid (herpes) gestationis. IgG1 was found to be the major IgG subclass in both serum and tissue, being detected in the sera of all pemphigoid gestationis patients studied.In pemphigoid and pemphigus, however, the distribution of IgG subclasses was heterogeneous, with IgG4 being the dominant autoantibody.Pemphigoid (herpes) gestationis factor, the circulating anti-basement membrane zone autoantibody thought to be pathogenic in pemphigoid gestationis, is therefore, an IgG1 antibody, with inferred complement binding capacity. Tissue damage in pemphigoid gestationis is apparently mediated by complement fixation which is detected via the classical complement cascade.

Cutaneous squamous cell carcinomas (cSCCs) are the second most frequent cancers in fair-skinned populations; yet, because of their genetic heterogeneity, the key molecular events in cSCC tumorigenesis remain poorly defined. We have employed single nucleotide polymorphism microarray analysis to examine genome-wide allelic imbalance in 60 cSCCs using paired non-tumour samples. The most frequent recurrent aberrations were loss of heterozygosity (LOH) at 3p and 9p, observed in 39 (65%) and 45 (75%) tumours respectively. Microdeletions at 9p23 within the protein tyrosine phosphatase receptor type D (PTPRD) locus were identified in a total of 9 (15%) samples, supporting a tumour suppressor role for PTPRD in cSCC. In addition, microdeletions at 3p14.2 were detected in 3 (5%) cSCCs, implicating fragile histidine triad (FHIT) gene as a possible target for inactivation. Statistical analysis revealed that well-differentiated cSCCs demonstrated significantly fewer aberrations than moderately and poorly differentiated cSCCs; yet, despite a lower rate of allelic imbalance, some specific aberrations were observed equally frequently in both groups. No correlation was established between the frequency of chromosomal aberrations and immune or human papillomavirus status. Our data suggest that well differentiated tumours are a genetically distinct subpopulation of cSCC.

Sebaceous carcinomas are rare cutaneous appendageal tumors that may occur sporadically or in association with an internal malignancy in Muir-Torre syndrome. In Muir-Torre syndrome microsatellite instability can often be demonstrated in tumor DNA as a result of an inherited mutation in one of several known mismatch repair genes; however, the role of microsatellite instability in sporadic sebaceous carcinomas has not been previously studied. In this report we describe the clinicopathologic characteristics of a series of unselected sebaceous carcinomas and examine them for the presence of microsatellite instability. Of 10 consecutive tumors identified over a 10 y period, only one was from a patient known to have Muir-Torre syndrome. Of the nine presumed sporadic cases, five were from four renal transplant recipients and four from otherwise healthy individuals. Microsatellite instability was demonstrable in three cases: in the Muir-Torre syndrome-associated tumor and in two tumors from transplant patients. Microsatellite instability was subsequently also found in a sebaceous carcinoma from a further transplant patient prospectively sought from another institution. The presence of microsatellite instability in post-transplant sebaceous carcinomas was associated with loss of expression of the mismatch repair protein hMSH2. In summary, sebaceous gland carcinomas, while characteristic of Muir-Torre syndrome, are commonly found outside this context. Among presumed sporadic cases, our data suggest they may be over-represented in immunosuppressed renal transplant recipients. The presence of microsatellite instability in transplant-associated lesions, together with loss of hMSH2 expression suggests that immunosuppression might unmask a previously silent Muir-Torre syndrome phenotype in some cases. Alternatively, there is experimental evidence to suggest that immunosuppressive drugs, most plausibly azathioprine, could select for the emergence of a mutator phenotype and thus predispose to the development of sebaceous carcinomas. The role of mismatch repair defects in other post-transplant skin malignancies remains to be established.

The influence of the sequential stages of conventional formaldehyde fixation and paraffin embedding of cutaneous tissue on monoclonal antibody labeling of cell surface antigens is described. The effects of variation in fixation time, dehydration, clearing, wax embedding, and enzyme treatment of cutaneous sections were examined. By curtailing fixation time, using cold ethanol dehydration, and limited cold clearing with xylene, immunoreactivity of several important monoclonal antibodies was retained. Wax embedding could be achieved at 58 degrees C for 1 h or by using low-melting-point wax at 42 degrees C for 3 h. Thus was derived an optimal processing procedure which afforded good tissue morphology and allowed reliable reproducible labeling by monoclonal antibodies to cell surface antigens.

SUMMARY The immunocytochemical identificatio n and characterization of indigenous dermal dendritic cells (dermal dendrocytes) using a rabbit polyclonal antibody to clotting enzyme factor XIII subunit A (FXIIIa) was carried out on normal and inflamed human cutaneous tissue. The immunophenotype of FXIIIa positive dendritic cells was analysed with a panel of r8 monoclonal antibodies using immunoperoxidase and double immunofluorescence staining techniques. The antibody against FXIIIa detected highly dendritic dermal cells located particularly in the upper reticular and papillary dermis. Double fluorescence microscopy showed that FXIIIa positive cells were bone marrow derived (HLe-i ^) and co-expressed monocyte, macrophage or antigen presenting cell markers (HLA-DR "^, LFA-I', HLA-DQ ', OKM5 *, Mo 1 ^ , Mono1 ^, Leu M3^). No labelling was obtained with cell markers for Langerhans cells (CDi), T lymphocytes (CD2), granulocytes (LeuMi) fibroblasts (Te7), intercellular adhesion moleculeI (ICAM-i) or endothelial cells (Factor VIII related antigen). Gamma interferon induced increased expression of HLA-DR and co-expression of ICAM-i on FXIIIa^ dermal dendritic cells in normal skin in organ culture. Moreover, in benign inflammatory dermatoses such as atopic eczema and psoriasis there was an increased number of FXIIIa ^,DR + , ICAM-I + cells in the upper dermis and foci of FXIIIa^ cells in the epidermis closely associated with lymphocytes. FXIIIa positive cells in human skin represent a specific population of bone-marrow dermal dendritic cells, distinct from Langerhans cells, that share some features common to mononuclear phagocytes (monocyte/macrophages). In addition, the detection of HLA-DQ on 48"n of FXIIIa" cells and the lack of OKMi in combination with high OKM5 expression suggests an antigen-presenting cell phenotype.