Pigmented skin lesions displaying regression features: Dermoscopy and reflectance confocal microscopy criteria for diagnosis.

Melanomas and nevi displaying regression features can be difficult to differentiate. To describe reflectance confocal microscopy features in benign and malignant pigmented skin lesions characterized by regression features in dermoscopy. Observational retrospective study. Inclusion criteria were presence of dermoscopic features of regression; availability of clinical, dermoscopic and RCM imaging; definite histopathologic diagnosis. The study sample comprised 217 lesions; 108 (49.8%) melanomas and 109 were benign lesions, of which 102 (47.0%) nevi and 7 (3.2%) lichen planus-like keratosis (lplk). Patients with melanoma were significantly older than those with benign lesions (61.9 ± 15.4 vs 46.1 ± 14.8; P < 0.001) and a higher proportion of melanomas displayed dermoscopic regression structures in more than 50% of lesion surface (n = 83/108; 76.9%; P < 0.001). On RCM examination, pagetoid cells were significantly more reported in melanoma group, than in benign lesions (86.1% vs 59.6%; P < 0.001) and were more frequently widespread distributed (65.6% vs 20.0%; P < 0.001) and both dendritic and roundish (36.6% vs 15.4%; P < 0.001) in shape. Aspecific architecture at the dermo-epidermal junction (DEJ) was more commonly seen among melanomas than benign lesions (23.1% vs 11.9%; P = 0.002) with higher presence of dendritic and both dendritic and roundish atypical cells at the DEJ (28.7% vs 18.3% and 19.4% vs 3.7%; P < 0.001, respectively). Focal pagetoid infiltration and ringed or clod patterns were more commonly seen in benign lesion. In conclusion, the correct interpretation of regressing lesions remains a challenge, assessing carefully the extent and characteristics of architectural and cytologic atypia on RCM is an additional piece of the complex puzzle of melanoma diagnosis.

A Deep Learning Approach to Vascular Structure Segmentation in Dermoscopy Colour Images.

BACKGROUND: Atypical vascular pattern is one of the most important features by differentiating between benign and malignant pigmented skin lesions. Detection and analysis of vascular structures is a necessary initial step for skin mole assessment; it is a prerequisite step to provide an accurate outcome for the widely used 7-point checklist diagnostic algorithm. METHODS: In this research we present a fully automated machine learning approach for segmenting vascular structures in dermoscopy colour images. The U-Net architecture is based on convolutional networks and designed for fast and precise segmentation of images. After preprocessing the images are randomly divided into 146516 patches of 64 × 64 pixels each. RESULTS: On the independent validation dataset including 74 images our implemented method showed high segmentation accuracy. For the U-Net convolutional neural network, an average DSC of 0.84, sensitivity 0.85, and specificity 0.81 has been achieved. CONCLUSION: Vascular structures due to small size and similarity to other local structures create enormous difficulties during the segmentation and assessment process. The use of advanced segmentation methods like deep learning, especially convolutional neural networks, has the potential to improve the accuracy of advanced local structure detection.

The relationship between naevus count, memory function and telomere length in the Twins UK cohort.

The presence of a skin-brain connection whereby alterations in the skin can inform on mechanisms underlying neurodegenerative diseases is increasingly recognized. In this study, we used a discovery (n = 321) and replication (n = 147) sample from the Twins UK population to test the association between naevus count and memory function, and its mediation by telomeres. Memory function was assessed in 1999 and 2009 using the paired associates learning test (PAL), while naevus count and leucocyte telomere length (LTL, assessed by the terminal restriction fragment assay) were measured once. Higher baseline naevus count was significantly associated with fewer errors at the baseline and follow-up PAL, as well as with change in PAL score over 10 years. This association was significantly attenuated after adjustment for LTL. The significant association between naevus count and PAL score was reproduced in the replication sample. These findings suggest that melanocytes might be used as model system to study the biological ageing pathways involved in neurodegeneration.

Complex Truncal Masses in the Setting of CLOVES Syndrome: Aesthetic and Functional Implications.

BACKGROUND: Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal abnormalities (CLOVES) is a complex overgrowth syndrome with dramatic aesthetic and functional implications. The truncal masses characteristic of CLOVES syndrome are described as vascular malformations or lipomatous lesions with variable vascular components. Herein, we describe our single-institution experience with surgical excision of CLOVES-related truncal masses and discuss future directions in treatment of these complex anomalies. METHODS: A single-institution retrospective review was performed for patients diagnosed with CLOVES syndrome. Patients undergoing excision of truncal vascular malformations were included. Outcome measures included perioperative characteristics [estimated blood loss (EBL), specimen size/anatomic location, blood-product requirement], as well as length-of-stay [LOS], and complication profile. Mean follow-up was 23.4 months (range 4.2-44). RESULTS: Three consecutive patients were reviewed, accounting for 4 surgical operations. One patient underwent two operations for two distinct masses. All lesions were located on the upper back or flank with various degrees of muscular involvement. One patient required no transfusions with an uneventful 2-day hospitalization. The remaining three patients had an EBL ranging from 1500 to 6450 mL, requiring 9-13 units of packed red blood cells and 5-8 units of fresh frozen plasma during LOS (averaging 5 days). Mean weight of resected masses was 6.26 lbs (range 2.04-12 lbs) and mass dimensions ranged between 1778.9 and 15,680 cm3. One patient with recurrence was subsequently treated with a combination of sclerotherapy and rapamycin, leading to significant mass reduction. CONCLUSIONS: Management of CLOVES syndrome requires a collaborative and multimodal approach. Although surgical debulking is one treatment option, non-invasive medical modalities and sclerotherapy should be considered prior to surgical resection. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Papular Epidermal Nevus with Skyline Basal Cell Layer (PENS): Three New Cases and Review of the Literature.

BACKGROUND/OBJECTIVE: Papular epidermal nevus with skyline basal cell layer (PENS) is a recently described type of epidermal nevus with characteristic histopathologic findings, mainly regular, rectangular acanthosis and a well-demarcated basal cell layer with clear palisading and separation between basal cell nuclei and the first row of Malpighian cell nuclei. Although the first reports described randomly distributed lesions appearing sporadically in otherwise healthy patients, cases of Blaschkoid distribution, lesions associated with extracutaneous manifestations, and familial cases have been reported. METHODS: We performed a review of the clinical charts of all patients with histologic diagnosis of PENS in our hospital. We evaluated epidemiologic, clinical, and histologic features. We then reviewed the literature with a particular emphasis on the presence or absence of extra-cutaneous associations. RESULTS: Three patients with PENS are described. One had a single lesion, one had three lesions, and one, a patient with mild developmental delay, a curved penis, and hypospadias, had multiple lesions. CONCLUSION: The probability of having extracutaneous manifestations is 6.3 times as great in individuals with more than four lesions. Therefore these patients may need closer follow-up.

Phenotype/genotype correlations in epidermal nevus syndrome as a neurocristopathy.

Epidermal nevus syndrome (ENS) is a term that encompasses several phenotypes defined by the association of an epidermal nevus with one or more congenital systemic anomalies, mainly ocular, osseous and cerebral. The two most frequent, keratinocytic nevus syndrome and linear sebaceous nevus syndrome, also correspond to the neurological phenotypes. They both exhibit overlapping and distinctive features but same etiology: post-zygotic mosaic mutations in RAS genes. Their pathogenesis is due to defective neural crest, further confirming that they are the same basic entity contradicting the concept that they are a group of heterogeneous syndromes with different etiologies. Both have been reported for more than a century. The sebaceous nevus, hallmark of linear sebaceous nevus syndrome, was defined by Jadassohn in 1895; the large number of subsequent contributors in defining this syndrome precludes the introduction of eponyms. Three other distinctive phenotypes within the spectrum of ENS with CNS involvement are CLOVES, SCALP and Heide's syndromes. Recognition of neurological phenotypes with multisystemic involvement should invoke multidisciplinary investigation and management. In some ENS phenotypes the association of melanocytic nevi with keratinocytic and sebaceous nevi, all sharing RAS mutations, predicts multisystemic involvement, in particular severe rickets and osseous anomalies. Phenotype is, therefore, the starting point for clinicians to guide genetic, neurological and other systemic investigations for patient management. The most frequent brain malformation in neurological phenotypes of ENS is hemimegalencephaly (HME). Epilepsy is the most frequent neurological symptom, in particular infantile spasms, with or without HME. The impact of neurological and systemic manifestations is related to onset and extent of the mutations. Timing of the mutation determines phenotype and severity. Proteus syndrome is a neurological phenotype of epidermal keratinocytic nevus syndrome not an independent, separate syndrome.

Epidermal nevus syndromes.

The term epidermal nevus syndrome (ENS) has been used to describe the association of epidermal hamartomas and extracutaneous abnormalities. Although many continue to use the term "ENS," it is now understood that this is not one disease, but rather a heterogeneous group with distinct genetic profiles defined by a common cutaneous phenotype: the presence of epidermal and adnexal hamartomas that are associated with other organ system involvement. One commonality is that epidermal nevi often follow the lines of Blaschko and it appears the more widespread the cutaneous manifestations, the greater the risk for extracutaneous manifestations. The majority of the extracutaneous manifestations involve the brain, eye, and skeletal systems. The CNS involvement is wide ranging and involves both clinical manifestations such as intellectual disability and seizures, as well as structural anomalies. Several subsets of ENS with characteristic features have been delineated including the nevus sebaceus syndrome, Proteus syndrome, CHILD syndrome, Becker's nevus syndrome, nevus comedonicus syndrome, and phakomatosis pigmentokeratotica. Advances in molecular biology have revealed that the manifestations of ENS are due to genomic mosaicism. It is likely that the varied clinical manifestations of ENS are due in great part to the functional effects of specific genetic defects. Optimal management of the patient with ENS involves an interdisciplinary approach given the potential for multisystem involvement. Of note, epidermal nevi have been associated with both benign and malignant neoplasms, and thus ongoing clinical follow-up is required.

Quantitative Imaging In Vivo of Functioning Lymphatic Vessels Around Human Melanoma and Benign Nevi.

OBJECTIVES: The density of functioning human lymphatics in vivo and of immunohistochemically defined lymphatics was quantified around melanomas, benign nevi, and matched normal skin, to assess the current lymphangiogenesis paradigm. We investigated whether histological and functioning density increased around melanomas compared with benign nevi or matched skin; whether functioning and histological density increased similarly; and whether larger increases occurred around metastatic melanomas. METHODS: Functioning density was quantified in vivo as the total amount of human dermal microlymphatics taking up fluorescent marker injected at the lesion margin. After tissue excision, perilesion histological density was quantified using podoplanin marker D2-40. RESULTS: Histological density was raised similarly around metastasising and non-metastasising melanomas compared with normal skin (+71%, p < 0.0001, n = 32); but was also raised significantly around benign nevi (+17%, p = 0.03, n = 20). In contrast, functioning lymphatic density was substantially reduced around the margins of melanomas (both metastasising and non-metastasising) compared with benign nevi (by 65%, p = 0.02) or normal skin (by 53%, p = 0.0014). CONCLUSIONS: Raised perilesion histological lymphatic density is not unique to melanoma but occurs also around benign nevi. The findings indicated that the number of functioning lateral lymphatics around human melanomas in vivo but not benign nevi is reduced, despite histologically increased numbers of lymphatics.

Blood DNA methylation, nevi number, and the risk of melanoma.

Germline mutations determining increased cutaneous malignant melanoma (CMM) risk have been identified in familial and sporadic CMM cases, but they account only for a small proportion of CMM cases. Recent evidence suggests that germline epimutations (e.g. DNA methylation alterations), which can be inherited similarly to genomic mutations and can be detected in normal body cells (including blood), might increase susceptibility to cancer. The aim of the study was to identify germline epimutations of genes that were found to be mutated in familial CMM (p16, p14, CDK4, MC1R, hTERT), immune and inflammatory genes (ICAM-1, TNFα), DNA mismatch repair gene (MLH1), and repetitive elements (ALU, LINE-1, HERV-w). We measured DNA methylation using bisulfite pyrosequencing in peripheral blood mononuclear cells from 167 CMM cases and 164 sex-matched and age-matched controls. We used multivariable logistic regression models to evaluate the association between methylation levels and CMM status or presence of dysplastic nevi. We found an association between the risk of CMM and peripheral blood mononuclear cell methylation levels of TNFα [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18], CDK4 (OR=0.76, 95% CI=0.64-0.91), and MLH1 (OR=1.12, 95% CI=1.02-1.22). In control participants, the risk of developing dysplastic nevi was associated with methylation levels of TNFα (OR=0.81, 95% CI=0.69-0.95), hTERT (OR=0.90, 95% CI=0.82-0.99), and ALU (OR=1.56, 95% CI=1.02-2.39). Epimutations in CMM susceptibility genes and in genes involved in response to oxidative damage are associated with the risk of developing CMM or dysplastic nevi. Further studies measuring methylation levels of these genes in prospectively collected samples are warranted to further elucidate their role in the development and progression of CMM.

Naevus sebaceus: a mosaic RASopathy.

Epidermal naevi are common cutaneous mosaic disorders that occur in 0.1-0.3% of live births. They are subdivided into keratinocytic and organoid naevi, the latter including naevus sebaceus (NS). Typically, NS develops as a yellowish-orange plaque on the scalp, and represents a hamartoma containing epidermal, sebaceous and apocrine elements. The histological features of NS sampled in childhood include hyperkeratosis, acanthosis, increased sebaceous lobules, and primitive hair follicles. During puberty, most lesions develop more prominent sebaceous and apocrine components. Subsequently, secondary tumours may occur in around 25% of NS; most lesions are benign (e.g. trichoblastomas, syringocystadenoma papilliferum or other basaloid proliferations), although malignant tumours arising within NS can occur (< 1%). Recently, somatic mosaicism has been shown, with activating Ras mutations in HRAS or KRAS in NS lesional keratinocytes (but not in adjacent nonlesional skin or dermal fibroblasts). These mutations lead to constitutive activation of the RAF-MEK-ERK and phosphoinositide 3-kinase signalling pathways, and result in increased cellular proliferation. Similar but more extensive mosaicism underlies Schimmelpenning-Feuerstein-Mims syndrome. The most common mutation is c.37G>C (p.Gly13Arg) in HRAS, which is present in > 90% of NS. This mutation also seems to be present in NS cases that develop secondary tumours, although no additional mutations (second hit) or other genetic events have yet been identified. Treatment of NS often involves prophylactic surgical excision, but the recent identification of key epidermal signalling abnormalities underlying the cell proliferation means that future development of new medical treatments for NS that target the aberrant signalling pathways may also be feasible.

Feasibility of skin surface elastography by tracking skin surface topography.

Recent advances have led to a multitude of image modalities being used for visualization of tissue stiffness. High-resolution images of tissue stiffness are desirable, as they have the potential to provide useful diagnostic information. A noncontact optical imaging method has the attractions of low cost, simplicity, and utility when skin contact is undesirable. However, previous optical techniques have required the application of paint or ink to the surface of the skin and so have required contact. Therefore, the present study assessed the feasibility of tracking skin surface topography to produce elastograms. The study showed, by analyzing a variety of silicone skin surface replicas from various body sites of subjects of different ages, that skin surface elastography by tracking surface topography would be feasible. The study further showed that the quality of the strain images can be optimized by measuring skin line pattern frequency. Skin samples with high skin line frequency will achieve best spatial resolution, in the order of 1 mm, comparable to contact techniques reported previously. A mechanically inhomogeneous silicone replica was then imaged, illustrating the technique's ability to detect strain contrast. Finally, the feasibility of implementing the technique in vivo was illustrated using a single pigmented skin lesion.

Wnt signaling potentiates nevogenesis.

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.

Nevus melanocíticos en el pie: indicación quirúrgica / Melanocytic nevus in the foot: surgical indication

La presencia de nevus melanocíticos en pie resulta muy frecuente en la población caucásica, así como en la región subungueal en personas de raza negra. Por ello resulta importante para los profesionales involucrados saber diferenciar la benignidad o malignidad de la lesión, así como establecer las indicaciones quirúrgicas (AU)

The presence of melanocytic nevi in the foot is very common in the caucasian population and in subungual region in blacks. It is therefore important for the professionals involved to differentiate between benign or malignant lesion, and to therefore take proper surgical action (AU)

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma.

Giant congenital naevi are pigmented childhood lesions that frequently lead to melanoma, the most aggressive skin cancer. The mechanisms underlying this malignancy are largely unknown, and there are no effective therapies. Here we describe a mouse model for giant congenital naevi and show that naevi and melanoma prominently express Sox10, a transcription factor crucial for the formation of melanocytes from the neural crest. Strikingly, Sox10 haploinsufficiency counteracts Nras(Q61K)-driven congenital naevus and melanoma formation without affecting the physiological functions of neural crest derivatives in the skin. Moreover, Sox10 is also crucial for the maintenance of neoplastic cells in vivo. In human patients, virtually all congenital naevi and melanomas are SOX10 positive. Furthermore, SOX10 silencing in human melanoma cells suppresses neural crest stem cell properties, counteracts proliferation and cell survival, and completely abolishes in vivo tumour formation. Thus, SOX10 represents a promising target for the treatment of congenital naevi and melanoma in human patients.

Intravitreal bevacizumab for choroidal neovascularization associated with choroidal nevus.

PURPOSE: To report 10 cases of occult choroidal neovascularization (CNV) associated with choroidal nevus managed with intravitreal bevacizumab. METHODS: Interventional case series. Each nevus was examined and imaged with fluorescein angiography, B-scan ultrasonography, and optical coherence tomography. Data were retrospectively analyzed to evaluate outcomes of treatment response and visual acuity. RESULTS: Nine patients presented with CNV overlying a chronic choroidal nevus with a posterior margin within 1.5 mm of the foveola. In the 10th patient, the posterior margin of the nevus was located 10 mm from the foveola with extension of subretinal fluid into the macula. The CNV was subfoveolar in four cases, juxtafoveolar in two cases, and extrafoveolar in four cases. Initial visual acuity was 20/20 to 20/50 in 5, 20/60 to 20/100 in 2, and 20/200 or worse in 3 cases. Clinical features included subfoveolar fluid in nine, exudation in five, and hemorrhage in four cases. Intravitreal bevacizumab (1.25 mg/0.05 cc) was injected with regression of CNV in all 10 cases using 2 to 14 injections (median 3 injections). In 2 eyes, after therapeutic response to bevacizumab later consolidation with photodynamic therapy (juxtafoveolar CNV) (n = 1) or conventional laser (extrafoveolar CNV) (n = 1) was provided. In the remaining 8 eyes, after discontinuation of bevacizumab, there was no recurrence of CNV over mean 10.1 months. At overall mean follow-up of 22.5 months, final visual acuity decreased by 1 line in 4 cases and improved by mean of 3 lines (range, 1-8 lines) in 6 cases. There were no adverse effects from bevacizumab injections. All 10 choroidal nevi remained stable. CONCLUSION: Intravitreal bevacizumab appears to be an effective treatment option for CNV secondary to choroidal nevus. In some cases, depending on the proximity of the CNV to the foveola, photodynamic therapy or conventional laser may be useful adjunctive therapy.

Immune reactions in benign and malignant melanocytic lesions: lessons for immunotherapy.

Spontaneous regression of benign and malignant melanocytic lesions can be a visible sign of immunosurveillance. In this review, we discuss different immune reactions against melanocytic lesions: halo nevus, Meyerson's nevus, regression in melanoma and melanoma-associated depigmentation. These entities present with particular clinical aspects, histology and evolution. In all entities, a melanocyte-specific T-cell reaction has been assumed but a different degree of melanocyte destruction is present. A focus on the immune responses in melanocytic lesions reveals several aspects of an adequate skin immunity and may help to identify the key points in the immune destruction of melanocytes. These insights can add to the knowledge of how to optimize immunotherapeutic strategies in melanoma.

Light scattering spectroscopy of human skin in vivo.

We present an in vivo study of the reduced scattering coefficient of normal skin and of common melanocytic nevi in Caucasian subjects. The spectral shape of the reduced scattering coefficient is described well by a power-law dependence on the wavelength, in accordance with previous studies of light scattering by biological tissues. We investigate statistical variations in the scattering spectrum slope and also identify an inherent correlation between scattering intensity and scattering spectral slope, observed mainly in normal skin. In addition, we do not find any significant differences between the scattering properties of normal skin and common melanocytic nevi. Finally, we also provide a short review of previously published studies reporting on the light scattering properties of human skin both in vivo and in vitro.