Degree of Actinic Elastosis Is a Surrogate of Exposure to Chronic Ultraviolet Radiation and Correlates More Strongly with Cutaneous Squamous Cell Carcinoma than Basal Cell Carcinoma.

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Phototherapy-induced elevation of serum level of melanoma inhibitory activity.

BACKGROUND: Phototherapy is a frequently used treatment modality for a variety of dermatologic diseases. UV radiation has different effects on the skin, for example increased production and release of cytokines and other proteins, and is involved in the initiation and progression of skin cancer. Objective of this clinical trial was to investigate potential systemic effects of UV phototherapy on cytokine profiles in blood. METHODS: In a prospective, mono-centric, one-armed study, the serum levels of the melanoma tumour marker "melanoma inhibitory activity" (MIA), Il-1α, Il-4, Il-6, Il-10, TNF-α and IFN-γ of 115 patients with different skin diseases were compared before and 24-48 hours as well as 2-4 weeks after the first phototherapy with PUVA (psoralen and ultraviolet A), UVA or UVB, or both. Data were analysed using linear mixed models. RESULTS: Estimated marginal means of MIA levels were 6.05 ng/mL (95%-CI: 5.37-6.72, range: 2.83-14.49) before the first treatment, which had significantly increased to 6.79 ng/mL 2-4 weeks after the first phototherapy (CI 95%: 6.12-7.47, range: 3.09-15.45; P = 0.0042). MIA levels 2-4 weeks after the first phototherapy were significantly higher than 24-48 hours after the first phototherapy (P = 0.0083). 2-4 weeks after the first treatment, TNF-α levels had decreased significantly (P = 0.033) more in patients with psoriasis who had responded well to phototherapy than in patients unresponsive to treatment. Serum levels of the other cytokines had not changed significantly. CONCLUSIONS: Short-term phototherapy significantly increased the serum levels of the melanoma tumour marker MIA. The potential clinical relevance of these findings (ie an increased risk of melanoma) is unclear and should be further investigated.

Fractional carbon dioxide laser resurfacing of skin grafts: long-term results of a prospective, randomized, split-scar, evaluator-blinded study.

BACKGROUND: Fractional ablative resurfacing is frequently used for treating atrophic and acne scars as well as for the early improvement of scars after surgery. No evidence-based clinical data on improving the appearance of skin grafts by fractional CO2 -laser resurfacing have been available so far. OBJECTIVES: The primary outcome parameter was the adaptation of the skin graft to the surrounding skin 2, 6, and 12 months after the second laser treatment. Secondary outcome parameters were melanin variation, skin roughness, resizing of the skin graft, and patient satisfaction with cosmetic results. METHODS: The randomized half of the skin graft was treated with the fractional CO2 -laser two times in a 4-week interval, whereby the first laser treatment was conducted 3-8 weeks after surgery. Two independent dermatologists assessed the adaptation of the treated area and the untreated control of the skin graft to the surrounding skin using follow-up pictures and an 11-point scale (0 representing no adaptation at all and 10 complete adaptation). RESULTS: Adaptation to the surrounding skin was significantly improved after laser therapy. The mean investigator ratings showed poor adaptation to the surrounding skin before the first treatment (treatment: 2.24 ± 1.00; control group: 1.95 ± 1.27; P < .001; n = 26) but significant improvement at the follow-up visits (8 weeks: treatment: 6.38 ± 1.47; control group 5.29 ± 1.27; P < .001; 6 months: treatment: 7.31 ± 1.24; control group 6.04 ± 0.91; 12 months: treatment: 7.6 ± 1.26; control group: 6.57 ± 1.02; n = 26). After fractional ablative laser treatment, appearance of the skin grafts was significantly improved for all time points. Profilometric analysis showed significantly reduced skin roughness 1 year after laser treatment compared to control (P = .003). Pigmentary irregularities were improved. Melanin distribution was significantly more uniform 1 year after laser treatment compared to control (P = .034). Patients were reasonably satisfied with both sides of the skin graft before treatment but more satisfied with the laser-treated side at the other time points (P < .001). CONCLUSIONS: Adaptation of the skin graft to the surrounding skin was significantly improved after ablative fractional skin resurfacing. Skin roughness and melanin variation were also improved. Patient satisfaction with the appearance of the skin graft was significantly higher after graft resurfacing. Thus, this treatment modality can be recommended for patients wishing to improve the appearance of their skin graft. Lasers Surg. Med. 50:1010-1016, 2018. © 2018 Wiley Periodicals, Inc.

KRAS, HRAS and EGFR Mutations in Sporadic Sebaceous Gland Hyperplasia.

Sporadic sebaceous gland hyperplasia (SGH) is a benign skin lesion, with a high prevalence in the general population. Although SGH has been attributed to both extrinsic and intrinsic factors, the underlying genetic changes have not yet been characterized. Recently, HRAS and KRAS mutations have been identified in sebaceous naevus, a hamartoma sharing histological characteristics with SGH. Therefore we screened 43 SGH for activating mutations in RAS genes and other oncogenes. We identified a wide spectrum of mutually exclusive activating HRAS (8/43), KRAS (11/43) and EGFR mutations (7/31) in altogether 60% of the lesions investigated. A RAS and EGFR wildtype status was found in 15 normal sebaceous glands in the head and neck area. Our findings indicate that activating HRAS, KRAS and EGFR mutations play a major role in the pathogenesis of sporadic SGH. These results support the concept that SGH is a true benign neoplasm rather than a reactive hyperplasia.

BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma.

Pyogenic granuloma (PG) is a common benign vascular skin lesion presenting as a rapidly growing angiomatous papule. The pathogenesis of most sporadic PGs and PGs associated with port wine stains (PWSs) remains elusive. We report that of 10 PGs secondarily arisen on a PWS, 8 showed a BRAF c.1799T>A (p.(Val600Glu)) and 1 a NRAS c.182A>G (p.(Gln61Arg)) mutation. The GNAQ c.548G>A mutation was identified in the PG and in the respective underlying PWS, indicating that PGs originate from cells of the PWS. In contrast to PG, 12 papulonodular lesions, which had developed in the PWSs of seven patients, showed a RAS and BRAF wild-type status. In sporadic PG we identified the BRAF c.1799T>A mutation in 3 of 25, a BRAF c.1391G>A mutation in 1 of 25, and a KRAS c.37G>C mutation in 1 of 25. Mutation-specific immunohistochemical detection of BRAF p.(Val600Glu) confirmed endothelial cells as carriers of the mutation in secondary and sporadic PG. Our study identifies the BRAF c.1799T>A mutation as a major driver mutation in the pathogenesis of, particularly, secondary PG. These data shed light on the hitherto undetermined genetic basis of PG and classify PG as a benign neoplasm.

Fractional carbon dioxide laser resurfacing of rhytides and photoaged skin--a prospective clinical study on patient expectation and satisfaction.

BACKGROUND: Fractional CO2 -laser resurfacing is increasingly used for treating rhytides and photoaged skin because of its favorable benefit-risk ratio. A key outcome measure and treatment goal in aesthetic laser therapy is patient satisfaction. However, few data are available on patient-reported outcomes after fractional ablative skin-resurfacing. OBJECTIVES: To compare patient expectations before and patient satisfaction after three fractional CO2 -laser treatments and to correlate objectively measured wrinkle reduction with patient satisfaction after treatment. METHODS: We investigated patient expectation and satisfaction using a 14-item questionnaire in 24 female patients. We assessed the skin-related quality of life and patient satisfaction with skin appearance. We profilometrically measured wrinkle size in four facial areas before and three months after treatment and investigated correlations between wrinkle reduction and patient satisfaction. RESULTS: The high patient expectations before treatment (ceiling effect) were actually slightly exceeded. The average score of 14 items delineating patient satisfaction with laser treatment was higher (4.64 ± 0.82; n = 24) than the respective expectations before treatment (4.43 ± 0.88; n = 24). Skin-related quality of life and patient satisfaction with skin appearance had significantly improved after the last treatment. Patients dissatisfied with their skin appearance before treatment (mean 2.1 ± 1.5; evaluated on a scale ranging from 0-6) were satisfied (mean 5.1 ± 1.2) (P < 0.001) with skin appearance at the follow-up. Patient satisfaction with skin appearance was not correlated to the profilometrically measured reduction of wrinkle size of any facial area. CONCLUSIONS: Our results show high patient satisfaction with ablative fractional skin resurfacing, also regarding improved self-esteem and self-satisfaction despite high pre-treatment expectations. Skin-specific quality of life had significantly improved. Thus, this treatment modality can be recommended for patients with photoaged skin wishing to improve skin appearance.

Activating mutations in the RAS/mitogen-activated protein kinase signaling pathway in sporadic trichoblastoma and syringocystadenoma papilliferum.

Trichoblastoma (TB) and syringocystadenoma papilliferum (SCAP) are both rare adnexal skin lesions occurring either sporadically or as secondary neoplasms in sebaceous nevi. TB and SCAP associated with sebaceous nevi have been shown to carry the same HRAS mutation as the underlying nevus. However, the genetic background of sporadic TB and SCAP has remained unknown. Therefore, we screened 18 sporadic TBs and 23 sporadic syringocystadenoma papillifera from 41 patients for the presence of activating mutations in RAS genes and other oncogenes. Using a RAS SNaPshot assay, HRAS mutations were detected in 2 (11%) of 18 sporadic TB and 6 (26%) of 23 sporadic syringocystadenoma papillifera. A KRAS mutation was identified in 1 sporadic SCAP. High-throughput oncogene mutation profiling furthermore identified BRAF V600E mutations in sporadic syringocystadenoma papillifera, which could be validated in 12 (52%) of 23 lesions using a BRAF SNaPshot assay. BRAF and RAS mutations were mutually exclusive in sporadic syringocystadenoma papillifera. No BRAF mutation could be detected in 3 syringocystadenoma papillifera secondarily arisen from a sebaceous nevus as well as in sporadic TB. In 14 lesions carrying an oncogenic mutation, nonlesional control tissue from the epidermal margin revealed a wild-type sequence, thus proving the somatic character of the mutation. Our results indicate that activation of the RAS-mitogen-activated protein kinase pathway by BRAF and RAS mutations contributes significantly to the tumorigenesis of sporadic SCAP and, less frequently, of sporadic TB.

CHILD syndrome with mild skin lesions: histopathologic clues for the diagnosis.

CHILD syndrome is an acronym signifying congenital hemidysplasia with ichthyosiform nevus and limb defects. A 27-year-old woman presented with chronic verrucous and hyperkeratotic skin lesions involving the left genital area, left hand and left foot since childhood. The histopathologic findings were consistent with verruciform xanthoma. In correlation with the clinical picture of a linear lesion, the diagnosis of CHILD nevus was made. Subsequent genetic analysis identified a germline c.324C>T (p.A105V) NSDHL mutation and confirmed a diagnosis of CHILD syndrome. This syndrome can be associated with only minimal clinical symptoms. The anatomical distribution of the lesions, a static clinical course and the typical histopathologic features of a CHILD nevus can serve as the clue to a diagnosis of CHILD syndrome in such cases.

Luminescent dual sensors reveal extracellular pH-gradients and hypoxia on chronic wounds that disrupt epidermal repair.

Wound repair is a quiescent mechanism to restore barriers in multicellular organisms upon injury. In chronic wounds, however, this program prematurely stalls. It is known that patterns of extracellular signals within the wound fluid are crucial to healing. Extracellular pH (pHe) is precisely regulated and potentially important in signaling within wounds due to its diverse cellular effects. Additionally, sufficient oxygenation is a prerequisite for cell proliferation and protein synthesis during tissue repair. It was, however, impossible to study these parameters in vivo due to the lack of imaging tools. Here, we present luminescent biocompatible sensor foils for dual imaging of pHe and oxygenation in vivo. To visualize pHe and oxygen, we used time-domain dual lifetime referencing (tdDLR) and luminescence lifetime imaging (LLI), respectively. With these dual sensors, we discovered centripetally increasing pHe-gradients on human chronic wound surfaces. In a therapeutic approach, we identify pHe-gradients as pivotal governors of cell proliferation and migration, and show that these pHe-gradients disrupt epidermal barrier repair, thus wound closure. Parallel oxygen imaging also revealed marked hypoxia, albeit with no correlating oxygen partial pressure (pO2)-gradient. This highlights the distinct role of pHe-gradients in perturbed healing. We also found that pHe-gradients on chronic wounds of humans are predominantly generated via centrifugally increasing pHe-regulatory Na+/H+-exchanger-1 (NHE1)-expression. We show that the modification of pHe on chronic wound surfaces poses a promising strategy to improve healing. The study has broad implications for cell science where spatial pHe-variations play key roles, e.g. in tumor growth. Furthermore, the novel dual sensors presented herein can be used to visualize pHe and oxygenation in various biomedical fields.

Low incidence of oncogenic EGFR, HRAS, and KRAS mutations in seborrheic keratosis.

Seborrheic keratosis (SK) represents a frequent epidermal skin tumor. Although lacking a malignant potential, these tumors reveal multiple oncogenic mutations. A previous study identified activating mutations in 89% of SK, particularly in FGFR3 and PIK3CA genes. The aim of this study was to identify further oncogenic mutations in human SK. Therefore, we screened for mutations in EGFR, FGFR2, PIK3R1, HRAS, KRAS, and NRAS genes using both Sanger sequencing of selected exons and a multiplex SNaPshot assay in 58 SK of 14 patients. We identified a somatic EGFR p.L858R mutation in 1 SK. Furthermore, the HRAS mutations p.G13R (2/58 SK) and p.Q61L (2/58 SK) were found. These mutations have not been described in human SK yet. In addition, 1 SK revealed the KRAS p.G12V mutation, which has already been reported in SK. No mutations were detected in FGFR2, PIK3R1, and NRAS genes. The results of this study suggest that activating mutations of EGFR, HRAS, and KRAS contribute to the pathogenesis of human SK, although at a lower frequency than FGFR3 and PIK3CA mutations. FGFR2, PIK3R1, and NRAS mutations obviously do not have a significant role in the development of SK.

An Internet-based survey on characteristics of laser tattoo removal and associated side effects.

Tattoo removal by laser therapy is a frequently performed procedure in dermatological practices. Quality-switched ruby, alexandrite, or Nd:YAG lasers are the most suitable treatment devices. Although these techniques are regarded as safe, both temporary and permanent side effects might occur. Little has been published on the frequency of complications associated with laser tattoo removal. We performed an Internet survey in German-speaking countries on characteristics of laser tattoo removal and associated side effects. A total number of 157 questionnaires entered the final analysis. Motivations for laser tattoo removal were mainly considering the tattoo as youthful folly (29%), esthetic reasons (28%), and 6% indicated medical problems. One third of participants were unsatisfied with the result of laser tattoo removal, and a complete removal of the tattoo pigment was obtained in 38% only. Local transient side effects occurred in nearly all participants, but an important rate of slightly visible scars (24%) or even important scarring (8%) was reported. Every fourth participant described mild or intense tan when the laser treatment was performed, and the same number of people indicated UV exposure following laser therapy, which should normally be avoided in these circumstances. As reported in the literature, nearly half of the participants experienced hypopigmentation in the treated area. Our results show that from the patients' point of view there is an important rate of side effects occurring after laser tattoo removal. Appropriate pretreatment counseling with regard to realistic expectations, possible side effects, and the application of test spots is mandatory to ensure patient satisfaction. Laser treatment should be performed by appropriately trained personnel only.

Adverse reactions after tattooing: review of the literature and comparison to results of a survey.

The number of tattooed people has substantially increased in the past years. Surveys in different countries reveal this to be up to 24% of the population. The number of reported adverse reactions after tattooing has also increased including infections, granulomatous and allergic reactions and tumors. However, the case reports do not reflect the frequency of adverse reactions. This review compares the medically documented adverse reactions published in 1991-2011 with the findings of a nation-wide survey that recently revealed the features and health problems associated with tattoos. To compare the data with the survey, the sex of patients was reported and the location and color of tattoos were evaluated. The results show clearly that colored tattoo inks are mainly responsible for adverse skin reactions and that tattoos on the extremities are involved most.

A randomized controlled trial to optimize indocyanine green-augmented diode laser therapy of capillary malformations.

BACKGROUND: Indocyanine green (ICG)-augmented diode laser therapy (ICG + DL) represents a new treatment modality for capillary malformations (CM). However, an increase of the ICG-concentration or the use of an intense pulsed light (IPL) device as light source may further optimize treatment outcomes in CM. OBJECTIVE: This proof-of-concept trial including 15 patients (skin type II to III) with CM evaluated the efficacy and safety of ICG-augmented diode laser therapy (808 nm) at a total dose of 4 mg/kg body weight (b.w.). Additionally, five patients with extensive CM received IPL therapy before and after ICG-administration (ICG + IPL). METHODS: ICG was intravenously administered to 15 patients with CM at a total dose of 4 mg/kg b.w. Immediately after ICG injection, diode laser pulses with different radiant exposures (20-110 J/cm(2) ) were applied as one single treatment. Five patients with extensive CM additionally received IPL (555-950 nm) therapy. Safety and efficacy were assessed both 1 and 3 months after the single treatment by a blinded investigator and the patient. Furthermore, color of the CM was objectively measured by means of a color meter (colorStriker™, Eduard Mathai GmbH, Hannover, Germany). Treatment with the flashlamp-pumped pulsed dye laser (FPDL) and the IPL alone (five patients) served as reference treatment. RESULTS: According to the assessment by the patients and the blinded investigator, the clearance rate was slightly better after ICG + DL therapy than after FPDL treatment (P = 0.1, P = 0.8). In one out of five patients, IPL with and without ICG injection induced poor to moderate clearance of CM and persisting erythema in another patient. The correlation between the visual assessment by the blinded investigator and the colorimetric measurements was poor. CONCLUSION: A minority of patients with CM may benefit from ICG + DL therapy, but efficacy cannot be improved by higher ICG doses.

Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell.

Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy.

Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study.

AIM: Both low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN. PATIENTS AND METHODS: Patients with resected melanoma ≥1.5mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 µg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3-4. RESULTS: Of 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73-1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80-1.32) and OS (HR 1.09, 95% CI 0.82-1.45). Peg-IFN was associated with higher rates of grade 3-4 AEs (47.3% versus 25.2%; p<0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN. CONCLUSION: This trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702.

A sprayable luminescent pH sensor and its use for wound imaging in vivo.

Non-invasive luminescence imaging is of great interest for studying biological parameters in wound healing, tumors and other biomedical fields. Recently, we developed the first method for 2D luminescence imaging of pH in vivo on humans, and a novel method for one-stop-shop visualization of oxygen and pH using the RGB read-out of digital cameras. Both methods make use of semitransparent sensor foils. Here, we describe a sprayable ratiometric luminescent pH sensor, which combines properties of both these methods. Additionally, a major advantage is that the sensor spray is applicable to very uneven tissue surfaces due to its consistency. A digital RGB image of the spray on tissue is taken. The signal of the pH indicator (fluorescein isothiocyanate) is stored in the green channel (G), while that of the reference dye [ruthenium(II)-tris-(4,7-diphenyl-1,10-phenanthroline)] is stored in the red channel (R). Images are processed by rationing luminescence intensities (G/R) to result in pseudocolor pH maps of tissues, e.g. wounds.

A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.

BACKGROUND: Current staging methods such as tumor thickness, ulceration and invasion of the sentinel node are known to be prognostic parameters in patients with malignant melanoma (MM). However, predictive molecular marker profiles for risk stratification and therapy optimization are not yet available for routine clinical assessment. METHODS AND FINDINGS: Using tissue microarrays, we retrospectively analyzed samples from 364 patients with primary MM. We investigated a panel of 70 immunohistochemical (IHC) antibodies for cell cycle, apoptosis, DNA mismatch repair, differentiation, proliferation, cell adhesion, signaling and metabolism. A marker selection procedure based on univariate Cox regression and multiple testing correction was employed to correlate the IHC expression data with the clinical follow-up (overall and recurrence-free survival). The model was thoroughly evaluated with two different cross validation experiments, a permutation test and a multivariate Cox regression analysis. In addition, the predictive power of the identified marker signature was validated on a second independent external test cohort (n=225). A signature of seven biomarkers (Bax, Bcl-X, PTEN, COX-2, loss of ß-Catenin, loss of MTAP, and presence of CD20 positive B-lymphocytes) was found to be an independent negative predictor for overall and recurrence-free survival in patients with MM. The seven-marker signature could also predict a high risk of disease recurrence in patients with localized primary MM stage pT1-2 (tumor thickness ≤2.00 mm). In particular, three of these markers (MTAP, COX-2, Bcl-X) were shown to offer direct therapeutic implications. CONCLUSIONS: The seven-marker signature might serve as a prognostic tool enabling physicians to selectively triage, at the time of diagnosis, the subset of high recurrence risk stage I-II patients for adjuvant therapy. Selective treatment of those patients that are more likely to develop distant metastatic disease could potentially lower the burden of untreatable metastatic melanoma and revolutionize the therapeutic management of MM.

Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.

Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.