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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.

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.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.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.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.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.

Reflectance confocal microscopy (RCM) allows for visualization of subsurface cellular detail in human skin and improves diagnostic accuracy. As the use of the technology expands, more features are being characterized. Here we show a confocal feature commonly associated with basal cell carcinoma appearing in a seborrheic keratosis.

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.

Early melanoma detection in sun-damaged skin can be a challenge. Clinically, some solar lentigines or flat seborrheic keratoses may be relatively indistinguishable from Lentigo Maligna. Reflectance Confocal Microscopy can now be used in the clinic to evaluate these lesions in vivo and increase biopsy accuracy. Spatial relationships of cells and architecture of associated skin structures play a critical role in appropriate diagnoses. As we move toward artificial intelligence using computer diagnostic platforms, it will be important to base algorithms on data with high diagnostic yield. We have undertaken efforts to create 3D reconstructions from sequential depths of confocal images of skin lesion in vivo in order to allow for more precise definition spatial relationships. These efforts have facilitated clearer evaluation of architectural changes at the dermal epidermal junction, location of cells around adnexal structures, and extent of melanocytic dendricity and diversity within the lesion. The use of color maps for efficient identification and accurate localization of cellular and architectural features of interest is another approach to advanced evaluation of confocal image data. We anticipate that these efforts will further improve accuracy for both human and computer diagnoses from reflectance confocal images. We appreciate generous support of the Theodora B Betz Foundation. Citation Format: Katharine L. Hanlon, James M. Grichnik. Reflectance confocal microscopy modeling of lentigo maligna [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1660.

Identification and removal of melanoma early in its development remains the most effective treatment. However, identification of early melanoma remains challenging and may result in unnecessary morbidity due to the excess excision of benign melanocytic nevi. Herein, we present a conceptual model of benign and malignant melanocytic growths. The potential differences in the location of the cell of origin as well as considerations for neoplasm progression are also reviewed. Several of the clinical tools currently available, the integration of information from those different sources, and approaches to set an optimum biopsy threshold are discussed. While early detection remains a challenge, significant progress has been made. Insight into melanoma growth processes and appropriate use of available tools can result in the detection of thinner melanomas while also decreasing overall biopsy rates.

Summary Background The identification of BRAF mutations in melanoma led to the development and implementation of new and effective therapies. Few clinical and histological features have been associated with this mutational status. Objectives The main objective of this study was to investigate clinical, histopathological and dermoscopic characteristics of primary melanomas according to BRAF or NRAS mutational status. Methods An observational retrospective study including melanoma dermoscopy images assessed for somatic mutations in BRAF and NRAS. Results Seventy-two patients were included, 30 women (42%) and 42 men (58%), mean age was 59 ± 15·51 years. BRAF-mutated melanomas were more frequently located on the trunk (n = 18, 64% for BRAF-mutated vs. n = 11, 29% for wild-type melanomas, P = 0·013). Histological ulceration was associated with the presence of BRAF mutations [odds ratio (OR) 3·141; 95% confidence interval (CI) 1·289–7·655; P = 0·002]. The Breslow index tended to be thicker in BRAF-mutated compared with wild-type (P = 0·086). BRAF mutations were present in 28 (39%) patients and only four cases were positive for NRAS mutations (6%), BRAF and NRAS mutations being mutually exclusive. The presence of dermoscopic peppering was associated with MAPK mutations (BRAF and NRAS) (OR 1·68; 95% CI 1·089–2·581; P = 0·015). Dermoscopic ulceration was also associated with BRAF mutations excluding acral and facial melanomas (OR 2·64; 95% CI 1·032–6·754). Conclusions This study showed a correlation between BRAF and NRAS status and dermoscopic findings of ‘peppering’ as an expression of regression and melanophages in the dermis, suggesting a morphological consequence of immune behaviour in BRAF-mutated melanomas.

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.br /br /emJ Drugs Dermatol./em2016;15(6):713-714.

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.

The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer–related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

Background Little is known about the dermoscopic features of scalp tumours. Objective To determine the dermoscopic features of scalp tumours. Methods Retrospective analysis of dermoscopic images of histopathologically diagnosed scalp tumours from International Dermoscopy Society members. Results A total of 323 tumours of the scalp from 315 patients (mean age: 52 years; range 388 years) were analysed. Scalp nevi were significantly associated with young age ( 65 years and sun damage. Atypical network and regression were predictive for thin (=1 mm) melanomas, whereas advanced melanomas (tumour thickness > 1 mm) revealed blue white veil, unspecific patterns and irregular black blotches or dots. Conclusions The data collected provide a new knowledge regarding the clinical and dermoscopy features of pigmented scalp tumours.

See related article, pages 1340–1347 Every therapy has toxic and therapeutic windows, and defining the side effects of any new therapeutic modality is the first order of business in the development of a treatment. With transformative therapies such as cell-based approaches, treatment side effects can be unpredictable and unanticipated. In some cases, experimental data raise serious concerns that must be appropriately managed. In the face of the promise and enthusiasm for cell-based therapy for heart disease, results from rodent experiments have consistently raised the specter of a dreaded side effect—can the use of stem cells lead to cancer, either directly or through promotion of existing early-stage neoplasms? Mesenchymal stem cells (MSCs) are a multipotent immunotolerant cell source that can be readily expanded into therapeutic quantities from a variety of tissues such as the bone marrow, cord blood, and fat, and as such their use in cell-based therapeutic strategies holds great promise.1 With regard to heart disease, accumulating preclinical2–11 and clinical studies12–15 demonstrate that MSC transplantation may be salutary for both acute myocardial infarction and cardiomyopathy with an acceptable risk profile. The translational development of cell-based therapy has required rigorous large-animal experimentation, recognizing inherent limitations with rodent experimentation. In this context, more than 500 large animals (swine, canine, and sheep) have been tested to assess the safety and efficacy of MSC therapeutics for treating heart disease with the results demonstrating that MSC transplantation is a safe and durable approach that may be more effective than bone marrow mononuclear cells.16 Importantly, large-animal work provides a phenotyping opportunity not available in rodents, and rigorous cardiac MRI (CMR) and histological analysis in porcine hearts supported the regenerative effects subsequently demonstrated in the adult human heart.12,15 The mechanism of action appears multifaceted, involving direct …

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.

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.

It is generally accepted that cutaneous nevogenesis is a localized event that occurs exclusively in the dermis and/or epidermis. However, the discovery of nevocytes circulating in the peripheral blood suggests that other, more systemic, benign metastatic processes could also be involved. The theoretical role of lymphatic and hematogenous dissemination of loosely adherent, immature nevus progenitor cells in the development of nodal nevi and eruptive melanocytic nevi will be reviewed.

Importance The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence. Objectives To outline key issues related to the management of CAN/DN: (1) biopsies of CAN and how positive margins arise, (2) whether incompletely excised DN evolve into melanoma, (3) current data on the outcomes of DN with positive histologic margins, (4) consensus recommendations, and (5) a proposal for future studies, including a large-scale study to help guide the management of DN with positive margins. Evidence Review The literature, including recent studies examining management and outcomes of DN with positive margins between 2009 to 2014, was reviewed. Findings A consensus statement by the PLS of the MPWG following review of the literature, group discussions, and a structured Delphi method consensus. Conclusions and Relevance This consensus statement reviews the complexities of management of CAN/DN. A review of the literature and 2 rounds of a structured Delphi consensus resulted in the following recommendations: (1) mildly and moderately DN with clear margins do not need to be reexcised, (2) mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than reexcised, and (3) observation may be a reasonable option for management of moderately DN with positive histologic margins without clinically apparent residual pigmentation; however, more data are needed to make definitive recommendations in this clinical scenario.

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-1β. Elevated levels of caspase-1 and IL-1β have been correlated with melanoma progression, and inhibitors of the inflammasome, caspase and IL-1β activity have all been shown to inhibit melanoma growth. Among many other potential actions, IL-1β 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.

As melanomas grow, they become more obvious and more deadly. As physicians, one of our goals is to identify and excise melanomas as early as possible. It is anticipated that 51, 400 new melanomas will be diagnosed in the United States this year. 2 It is also estimated that there are 4 billion melanocytic nevi, 8 or roughly 90, 000 nevi, for every melanoma. Although it is critical not to miss an early melanoma, it is also important not to indiscriminately remove benign nevi given the scarring, medical costs, and associated surgical risks. Distinguishing an early melanoma from a benign nevus can present quite a challenge, and many factors must be considered in deciding whether a lesion should be excised. These factors include a reported history of change by the patient, the anxiety level of the patient, patient or family history of melanoma, physical examination revealing irregular features (visible or palpable), how different the lesion is from the average size of the patient's lesions, and documentation of change. Dermatoscopy allows for a more detailed visual physical examination of a lesion and thereby may allow for identification of structural details that will favor a malignant or benign diagnosis. Sometimes even with dermatoscopy, however, identification of a malignant lesion can be difficult. 5 This review illustrates lesions in which the dermatoscopic diagnosis of melanoma or not melanoma can be a challenge.

BACKGROUND There is good prognostic correlation for the two microstaging systems, Breslow depth and Clark level, commonly used to stage melanomas. Many investigators have reported that Breslow depth is the superior microstaging method. Although Clark level has been dropped from most of the proposed American Joint Committee on Cancer (AJCC) melanoma staging system, the AJCC system still includes Clark Level IV as a criterion for upstaging thin melanomas. The authors sought to determine whether this is appropriate, based on melanoma patient data in the Duke Comprehensive Cancer Center database. METHODS Of the 8833 patients registered between January 1, 1970 and December 31, 1995, complete data on Breslow depth and Clark level was available for 4560 patients who were without nodal or metastatic disease at presentation. Ten-year survival was measured from the date of excision of the primary tumor until death from melanoma and analyzed using Kaplan–Meier and Cox proportional hazard methodologies. RESULTS When analyzed separately, both increased Breslow thickness and Clark level correlated with shorter survival times. During subgroup analysis, Breslow thickness remained a significant prognostic indicator of survival at Clark Levels III and IV. Conversely, at narrow levels of Breslow thickness (i.e., 0–0.75 mm, > 0.75 –1.0 mm, > 1.0–1.5 mm) survival times were indistinguishable between Clark Levels III and IV. For the broader Breslow thickness interval of 0–1.0 mm, a barely significant difference between Clark Levels III and IV could be obtained. However, for this thickness range, even greater differences in survival could be obtained by merely comparing Breslow subgroups (i.e., ≤ 0.8 mm vs. > 0.8–1.0 mm, ≤ 0.9 mm vs. > 0.9–1.0 mm). CONCLUSION The authors' data suggested that, after controlling for Breslow depth, Clark level was not a good prognostic indicator for survival. If the AJCC's objective is to design a classification system that will reliably predict the higher risk melanomas, then the system should be based on tumor thickness, which is clearly a better prognostic indicator, and should not be modified because of Clark level. Cancer 2001;91:983–91. © 2001 American Cancer Society.

Dendritic cells (DCs) are potent inducers of cytotoxic T lymphocytes (CTLs) when pulsed with an antigenic peptide or tumor lysate. In this report, we have used liposome-mediated gene transfer to examine the ability of plasmid DNA encoding the human melanoma-associated antigen gp100 to elicit CD8(+) and CD4(+) T-cell responses. We also compared the efficacy between gp100 gene-modified DCs and naked DNA (pCDNA3/gp100)-based vaccines at inducing anti-tumor immunity. DCs were generated from murine bone marrow and transfected in vitro with plasmid DNA containing the gp100 gene. These gp100-modified DCs (DC/gps) were used to stimulate syngeneic naive spleen T cells in vitro or to immunize mice in vivo. Antigen-specific, MHC-restricted CTLs were generated when DC/gps were used to prime T cells both in vitro and in vivo. Thus, these CTLs were cytolytic for gp100-transfected syngeneic (H-2(b)) tumor MCA106 (MCA/gp) and vaccinia-pMel17/gp100-infected syngeneic B16 and MCA106, but not parental tumor MCA106 and B16, or gp100-transfected allogeneic tumor P815 (H-2(d)). Immunization with DC/gp protected mice from subsequent challenge with MCA/gp but not parental MCA106. Antibody-mediated T-cell subset depletion experiments demonstrate that induction of CTLs in vivo is dependent on both CD4(+) and CD8(+) T cells. Furthermore, DC/gp immunization elicits an antigen-specific CD4(+) T-cell response, suggesting that DC/gps present MHC class II epitopes to CD4(+) T cells. In addition, our data show that gene-modified, DC-based vaccines are more effective than the naked DNA-based vaccines at eliciting anti-tumor immunity in both prophylactic and therapeutic models. These results suggest that the use of DCs transfected with plasmid DNA containing a gene for TAA may be superior to peptide-pulsed DCs and naked DNA-based vaccines for immunotherapy and could provide an alternative strategy for tumor vaccine design.

Wang et al. point to the existance of a common progenitor tumor stem cell that gives rise to genomically unstable progeny in malignant melanoma. Although it is not known what creates this genomic instability, given the presence of testis antigens in melanoma, it is tempting to speculate that it is caused by a collision of meiotic and mitotic pathways.

As described in this issue, Alexeev and Yoon introduced a Kit-activating mutation into melanocytes. Although mitogenic in mast cells, this mutation was motogenic in melanocytes. Further, melanocytes had a reduced proliferative rate and were less differentiated. The disparate response may be due to differences in the cellular milieu of melanocytes and may have implications for normal melanocytic integration into the epidermis, nevogenesis, and melanoma.

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 skin is believed to harbor a reservoir population of precursor melanocytes. It has been difficult to identify these putative cells experimentally, because they lack phenotypic features that define mature melanocytes. We have evaluated expression of the KIT tyrosine kinase receptor, which is critical for melanocyte development, as a possible marker of these cells. Sections of human skin were evaluated with single- and double-immunolabeling techniques. KIT-reactive dendritic cells were identified in the basal layer of the epithelia and were most numerous in the follicular infundibula and the rete ridges. These cells were located on the epithelial side of the basement membrane and lacked expression of cytokeratin and mast cell tryptase. The location of the KIT-reactive cells was distinctly different from that of Langerhans cells (identified with anti-CD1a) or Merkel cells (identified with CAM 5.2). Within the epidermis and upper follicular infundibulum the majority of the KIT-reactive dendritic cells also coexpressed TRP-1, a marker present in differentiated melanocytes. In the deeper follicular regions, the coexpression of TRP-1 in the KIT-reactive cells was absent. Throughout the epidermis and follicle, however, the KIT-reactive cells coexpressed BCL-2, a marker known to be increased in melanocytes. Thus, KIT expression reveals a population of intraepithelial cells that have immunophenotypic characteristics of mature melanocytes within the upper epithelial regions, but lack the differentiated Melanocytic phenotype within the deeper follicular regions. We propose that these KIT(+), BCL-2(+), and TRP-1(−) cells constitute a precursor melanocyte reservoir of human skin.