Reflectance confocal microscopic visualization of melanocytic bodies in the stratum corneum overlying acral lentiginous melanoma.

BACKGROUND: We present a case of RCM evaluation of ALM surgical margins demonstrating intracorneal melanocytic bodies overlying subsequently confirmed melanoma in situ by histopathology. CASE PRESENTATION: A 73-year-old male with a history of acral lentiginous melanoma (ALM) of the right great toe presented to our clinic for evaluation of positive surgical margins. The positive margin was localized for examination and subsequent biopsy with reflectance confocal microscopy (RCM) which allowed targeted re-resection of the area of concern. Three punch biopsies were obtained in the area of concern, which confirmed residual melanoma in situ. Immunostains confirmed the cellular remnants in the stratum corneum were melanocytic. To correlate the intra stratum corneum findings seen with confocal to the histopathology, a 3D rendering of a stack of images was used to demonstrate the location. DISCUSSION: Typically, acral surfaces are challenging to examine with RCM due to the limited ability of light to penetrate thickened stratum corneum; however, we observed unique cellular features with confocal. Scattered hyper-reflective pleomorphic cells consistent with melanocytes were observed in the stratum corneum, although the visualized underlying epidermis appeared normal. Confocal microscopy may aid in diagnosis and management of ALM, especially in the context of positive surgical margins.

Improving dermal level images from reflectance confocal microscopy using wavelet-based transformations and adaptive histogram equalization.

OBJECTIVES: Reflectance confocal microscopy (RCM) generates scalar image data from serial depths in the skin, allowing in vivo examination of cellular features. The maximum imaging depth of RCM is approximately 250 µm, to the papillary dermis, or upper reticular dermis. Frequently, important diagnostic features are present in the dermis, hence improved visualization of deeper levels is advantageous. METHODS: Low contrast and noise in dermal images were improved by employing a combination of wavelet-based transformations and contrast-limited adaptive histogram equalization. RESULTS: Preserved details, noise reduction, increased contrast, and feature enhancement were observed in the resulting processed images. CONCLUSIONS: Complex and combined wavelet-based enhancement approaches for dermal level images yielded reconstructions of higher quality than less sophisticated histogram-based strategies. Image optimization may improve the diagnostic accuracy of RCM, especially for entities with dermal findings.

Diagnostic application of cyclin D1 fluorescent in situ hybridization for histologically undetermined early lesions of acral melanoma in situ: A case series.

Histologically undetermined early acral melanoma in situ (HUAMIS) is rare but a diagnostic challenge, being clinically and dermoscopically MIS (late onset, a large size (>7 mm), parallel ridges pattern) but microscopically without recognizable cytological atypia. Cyclin D1 (CCND1) gene amplification is a genetic aberration occurring in the early radial growth phase of AMs and could thus help determine malignancy for this disease. We determine the value of CCND1 amplification by FISH as a diagnostic marker for HUAMIS. CCND1 amplification was examined in paraffin-embedded skin biopsies and excisions using a dual-probes fluorescence in situ hybridization (FISH) (11q13 and CEP11). One FISH-negative case 6 was additionally examined by Mypath Melanoma (qRT-PCR). Seventeen cases (12 dysplastic nevi, 3 AMIS, and 2 invasive AM) were served as negative controls for FISH. All six patients (4 females and 2 males) were Hispanic. Pigment lesions were on the left plantar foot (4), right third finger palm (1), and right thumb subungual (1). All cases showed similar clinical and dermoscopical characteristics, including late onset (50 to 74 years old), long duration (from 2 to 15 years), large-sized pigments (from 16 to 40 mm), and a parallel ridge pattern. Junctional melanocytes with no or minimal atypia from five cases showed CCND1 amplifications. Four of 5 cases were received 1st or/and 2nd wide excisions, which demonstrated foci of histologically overt MIS. One FISH-negative case 6 demonstrated "likely malignancy" scores (>2) by Mypath Melanoma (qRT-PCR). None of negative controls showed the amplification. We propose here a simple CCND1 FISH is a practical diagnostic test to determine the malignancy of the very early progression phase of AM preceding histopathologically defined MIS. Cases presented here could be an indolent subtype of AMIS characterized by carrying a long latent radial growth phase without vertical growth, mimicking lentigo maligna.

Methods of Melanoma Detection.

Detection and removal of melanoma, before it has metastasized, dramatically improves prognosis and survival. The purpose of this chapter is to (1) summarize current methods of melanoma detection and (2) review state-of-the-art detection methods and technologies that have the potential to reduce melanoma mortality. Current strategies for the detection of melanoma range from population-based educational campaigns and screening to the use of algorithm-driven imaging technologies and performance of assays that identify markers of transformation. This chapter will begin by describing state-of-the-art methods for educating and increasing awareness of at-risk individuals and for performing comprehensive screening examinations. Standard and advanced photographic methods designed to improve reliability and reproducibility of the clinical examination will also be reviewed. Devices that magnify and/or enhance malignant features of individual melanocytic lesions (and algorithms that are available to interpret the results obtained from these devices) will be compared and contrasted. In vivo confocal microscopy and other cellular-level in vivo technologies will be compared to traditional tissue biopsy, and the role of a noninvasive "optical biopsy" in the clinical setting will be discussed. Finally, cellular and molecular methods that have been applied to the diagnosis of melanoma, such as comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), will be discussed.

Acral melanocytic lesions in the United States: Prevalence, awareness, and dermoscopic patterns in skin-of-color and non-Hispanic white patients.

BACKGROUND: Acral lentiginous melanoma has increased mortality compared with other melanoma subtypes and disproportionately affects ethnic minorities. Acral melanocytic lesions have not been well studied in diverse populations of the United States. OBJECTIVE: We sought to assess the prevalence, awareness, and dermoscopic patterns of acral melanocytic lesions in skin-of-color and non-Hispanic white patients. METHODS: We prospectively examined the palms and soles of 1052 patients presenting to dermatology clinics in New York, NY, and Miami, FL, from October 2013 to April 2015. RESULTS: Acral melanocytic lesions were observed in 36% of our cohort. Skin-of-color patients were more likely to have acral melanocytic lesions than non-Hispanic white patients (P < .01). Acral melanocytic lesions correlated with increased mole counts, particularly on non-Hispanic white patients. The majority of lesions demonstrated benign dermoscopic patterns. We observed 2 lesions with the parallel ridge pattern in our cohort, both found to be atypical nevi on biopsy specimen. Patients often lacked awareness of the presence of their lesions. LIMITATIONS: Interobserver variability in assessing dermoscopic patterns is a limitation. CONCLUSIONS: Melanocytic lesions of the palms and soles are common, particularly in a cohort of multiple ethnicities from the United States. Dermoscopy of acral lesions is an important clinical tool for diagnosis and management of these lesions.

Utilization of Optical Coherence Tomography in the Evaluation of Cherry Hemangiomas.

Cherry hemangiomas are common vascular proliferative lesions that can be concerning from a cosmetic perspective. Laser therapy is often used to eradicate cherry hemangiomas, but some lesions require multiple treatments or do not resolve at all. The suboptimal response to laser treatment may be due to limitations in penetration depth by vascular lasers such as the pulsed dye laser. Optical coherence tomography is a low-energy, light-based imaging device that can evaluate the depth and extent of vascular lesions such as cherry hemangiomas by allowing visualization of tissue structure and blood vessel architecture, which cannot be appreciated by clinical or dermatoscopic examination alone. We present optical coherence tomography images of a cherry hemangioma to demonstrate the precision and resolution of this imaging modality. Optical coherence tomography provides valuable information that has the potential to predict response to laser therapy without unnecessary attempts. Future prospective studies will determine its value for this purpose.

J Drugs Dermatol. 2016;15(6):713-714.

Do inflammatory pathways drive melanomagenesis?

Inflammatory pathways serve to protect the host and promote tissue healing/repair; however, over-activation or dysregulation can be pathological with unintended consequences including malignant progression. A correlation between inflammation and cancer has been well established, and anti-inflammatory medications have been shown to be chemopreventive in certain malignancies. Data are now becoming available that outline an inflammatory pathway that may have a critical role in melanomagenesis. ATP-regulated membrane channels/receptors P2X7 and PANX1 have been directly implicated in melanoma tumor growth. Among other potential effects, opening of the P2X7/PANX1 channel results in activation of the NALP3 inflammasome, which in turn leads to caspase-1 activation and increased levels of activated IL-1ß. Elevated levels of caspase-1 and IL-1ß have been correlated with melanoma progression, and inhibitors of the inflammasome, caspase and IL-1ß activity have all been shown to inhibit melanoma growth. Among many other potential actions, IL-1ß increases cyclooxygenase-2 expression leading to local increases in inflammatory mediators such as prostaglandin E2 (PGE2). Anti-inflammatory medications targeting the end of this pathway have had positive results for certain cancers but overall remain mixed for melanoma. A better understanding of the pathways and appropriate intervention points may help direct future therapies. In this viewpoint, we will review data and attempt to model an inflammatory pathway that may be critical for melanomagenesis and propose future directions for exploration.

Melanoma's high C>T mutation rate: is deamination playing a role?

The majority of melanoma mutations are C>T transitions, and most bear UV signatures. However, other process may contribute to the high C>T mutation rate. Okura et al., have demonstrated immunohistochemical evidence of deaminating enzymes, activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3B (APOBEC3B) in melanoma. Both have been implicated in cancer. While further validation is necessary, these findings warrant consideration of a role for deamination in melanomagenesis. Deamination primarily drives C>T transitions. Compared with trunk/extremity melanomas, acral melanomas display a significantly higher percentage of 'spontaneous' and 'AID' mutation signature events suggesting deamination may be particularly important in this subgroup.

How, and from which cell sources, do nevi really develop?

Melanocytic neoplasms are a diverse group of benign and malignant tumors with variable clinical features. While some models still promote the epidermal melanocyte as the origin of melanocytic neoplasms, clinical findings are inconsistent with this theory for the majority of tumors. Despite advances in naevus and melanoma biology, the location and differentiation status of the cell of origin remains undefined. Germ line genetics, biological state and cellular location of the mutated cell, as well as local environmental factors all likely play a role in the development of melanocytic neoplasms. Herein, we will review potential models for melanocytic neoplasia and discuss research challenges and opportunities.

Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers.

Hair graying holds psychosocial importance and serves as an excellent model for studying human pigmentation and aging in an accessible miniorgan. Current evidence suggests that graying results from an interindividually varying mixture of cumulative oxidative and DNA damage, excessive mTORC1 activity, melanocyte senescence, and inadequate production of pigmentation-promoting factors in the hair matrix. Various regulators modulate this process, including genetic factors (DNA repair defects and IRF4 sequence variation, peripheral clock genes, P-cadherin signaling, neuromediators, HGF, KIT ligand secretion, and autophagic flux. This leads to reduced MITF- and tyrosinase-controlled melanogenesis, defective melanosome transfer to precortical matrix keratinocytes, and eventual depletion of hair follicle (HF) pigmentary unit (HFPU) melanocytes and their local progenitors. Graying becomes irreversible only when bulge melanocyte stem cells are also depleted, occurring later in this process. Distinct pigmentary microenvironments are created as the HF cycles: early anagen is the most conducive phase for melanocytic reintegration and activation, and only during anagen can the phenotype of hair graying and repigmentation manifest, whereas the HFPU disassembles during catagen. The temporary reversibility of graying is highlighted by several drugs and hormones that induce repigmentation, indicating potential target pathways. We advise caution in directly applying mouse model concepts, define major open questions, and discuss future human antigraying strategies.

Influence of time on dermoscopic diagnosis and management.

BACKGROUND/OBJECTIVES: Dermoscopy aids in clinical decision-making. However, time pressure is a common reason precluding its use. We evaluated the effect of time on lesion recognition and management decisions utilising clinical and dermoscopic images. METHOD: In all, 100 dermoscopic images were presented to 15 dermatologists with experience in dermoscopy and seven non-experts (dermatology residents). Each lesion was displayed thrice in succession. The dermoscopic image was initially presented for 1 s (t1). The same dermoscopic image was shown again without time constraints (t2) and then a final time with additional images of the clinical context (t3). Participants provided a diagnosis, their level of confidence and biopsy predilection after evaluating each image. RESULTS: For benign lesions, both groups rarely changed their diagnosis. However, an improvement in the number of correct benign diagnoses was observed when the lesion was shown in a clinical context. For malignant lesions, both groups improved when more time and clinical context was given; nevertheless, non-experts were more likely to change the diagnosis towards the correct one as more time was given and tended to perform more biopsies, in particular of benign lesions. Limitations were a small number of participants and an artificial study setting. CONCLUSION: Dermoscopy uses analytical and non-analytical reasoning approaches. We suggest that non-analytical reasoning is employed when rapid clinical decisions need to be made, especially during the evaluation of benign lesions. We conclude that dermoscopy is relatively rapid and non-time-consuming technique that adds relevant information and guides clinicians towards appropriate management decisions.

Dermoscopy and skin imaging light sources: a comparison and review of spectral power distribution and color consistency.

Significance: Dermoscopes incorporate light, polarizers, and optical magnification into a handheld tool that is commonly used by dermatologists to evaluate skin findings. Diagnostic accuracy is improved when dermoscopes are used, and some major artificial intelligence (AI) projects have been accomplished using dermocopic images. Color rendering consistency and fidelity are crucial for clinical diagnostics, AI, and image processing applications. Aim: With many devices available on the market, our objective was to measure the emission spectra of various dermoscopes, compare them with other light sources, and illustrate variations in reflected colors from images of a reference sample. Approach: A spectrometer measured the spectral power distribution (SPD) produced by four dermoscope models and three alternate light sources, illustrating differences in the emission spectra. Most dermoscopes use light-emitting diodes (LEDs), which are inconsistent when compared with one another. An LED was compared with halogen, xenon-arc, and daylight sources. Images of a micro ColorChecker were acquired from several sources, and three specific colors were selected to compare in CIELAB color space. Color consistency and color fidelity measured by color rendering index (CRI) and TM-30-18 graphical vectors show variation in saturation and chroma fidelity. Results: A marked degree of variation was observed in both the emission and reflected light coming from different dermoscopes and compared with other sources. The same chromophores appeared differently depending on the light source used. Conclusions: A lack of uniform illumination resulted in inconsistent image color and likely impacted metamerism and visibility of skin chromophores in real-world settings. Artificial light in skin examinations, especially LEDs, may present challenges for the visual separation of specific colors. Attention to LEDs SPD may be important, especially as the field increases dependency on machine/computer vision.