International Skin Imaging Collaboration-Designated Diagnoses (ISIC-DX): Consensus terminology for lesion diagnostic labeling.

BACKGROUND: A common terminology for diagnosis is critically important for clinical communication, education, research and artificial intelligence. Prevailing lexicons are limited in fully representing skin neoplasms. OBJECTIVES: To achieve expert consensus on diagnostic terms for skin neoplasms and their hierarchical mapping. METHODS: Diagnostic terms were extracted from textbooks, publications and extant diagnostic codes. Terms were hierarchically mapped to super-categories (e.g. 'benign') and cellular/tissue-differentiation categories (e.g. 'melanocytic'), and appended with pertinent-modifiers and synonyms. These terms were evaluated using a modified-Delphi consensus approach. Experts from the International-Skin-Imaging-Collaboration (ISIC) were surveyed on agreement with terms and their hierarchical mapping; they could suggest modifying, deleting or adding terms. Consensus threshold was >75% for the initial rounds and >50% for the final round. RESULTS: Eighteen experts completed all Delphi rounds. Of 379 terms, 356 (94%) reached consensus in round one. Eleven of 226 (5%) benign-category terms, 6/140 (4%) malignant-category terms and 6/13 (46%) indeterminate-category terms did not reach initial agreement. Following three rounds, final consensus consisted of 362 terms mapped to 3 super-categories and 41 cellular/tissue-differentiation categories. CONCLUSIONS: We have created, agreed upon, and made public a taxonomy for skin neoplasms and their hierarchical mapping. Further study will be needed to evaluate the utility and completeness of the lexicon.

Review of talimogene laherparepvec: A first-in-class oncolytic viral treatment of advanced melanoma.

Talimogene laherparepvec (T-VEC) is an oncolytic virus based on herpes simplex virus type 1 approved for intralesional treatment of advanced melanoma. In this article, we review the clinical literature on T-VEC for advanced melanoma and provide a practical approach to using T-VEC in the dermatologic surgery and oncology clinic. PubMed was used to conduct a systematic literature review of articles describing the structure, basic science, and clinical and therapeutic properties of T-VEC. The national clinical trials database was also searched for T-VEC clinical trials. Phase I to III clinical trials and early real-world experience have shown the efficacy of T-VEC in advanced melanoma as single or combination therapy with tolerable adverse effects. We conclude that with a standardized clinical approach and training, dermatologists can pave the way in using T-VEC and future oncolytic virus therapies in appropriate clinical scenarios.

A comparison of skin cancer screening and treatment costs at a Massachusetts cancer center, 2008 versus 2013.

BACKGROUND: Temporal analyses of skin cancer costs are needed to examine how expenditure differences between diagnoses are changing. OBJECTIVE: To tabulate the costs of skin cancer-related care (SCRC), including both screening and treatment, at an academic cancer center at 2 time points. METHODS: Cost data (insurance and patient payments) at an academic cancer center from 2008 and 2013 were queried for International Classification of Diseases, Ninth Revision, codes pertaining to skin cancer. Screening costs were separated from treatment costs through associated Current Procedural Terminology codes. RESULTS: The total annual cost of SCRC increased by 64%, the number of patients receiving SCRC increased by 45%, and the mean cost per patient treated increased by 13%. Screening accounted for 17% and 16% of total annual costs in 2008 and 2013, respectively. The mean cost per patient with melanoma increased by 84%, which was the largest increase among skin cancer diagnoses. In 2013, the few patients with melanoma who were treated with ipilimumab (n = 48 [4% of patients with melanoma]) accounted for 42% of melanoma treatment costs and 20% of SCRC costs. LIMITATIONS: Prescription costs were unavailable. CONCLUSIONS: Melanoma costs have increased as a result of the introduction of ipilimumab. Ongoing studies are needed to monitor the cost-effectiveness of SCRC at a national level.

Utilizing non-ablative fractional photothermolysis prior to ALA-photodynamic therapy in the treatment of acne vulgaris: a case series.

Aminolevulinic acid (ALA) photodynamic therapy (PDT) is an emerging modality in the treatment of acne. While ablative fractional lasers have been used to enhance drug delivery into the epidermis, recent evidence suggests that non-ablative fractional photothermolysis may also improve uptake of ALA. We explored the use of non-ablative 1550 nm laser as a safe alternative in the delivery of ALA prior to red-light PDT for refractory inflammatory and cystic acne. Subjects referred for treatment of acne refractory to several topical and oral regimens, including isotretinoin, were pre-treated with non-ablative fractional photothermolysis (NAFP). This was followed by 20 % ALA application with an incubation time of 1-3 h and then exposure to 50-100 J/cm2 red light. Follow-up was at 1, 3, and 6 months. In all three cases, patients demonstrated marked reduction in inflammatory lesions. Two subjects had remission of acne after a single combination treatment. Non-ablative fractional laser applied immediately prior to PDT may be used in the treatment of acne with minimal side effects and fewer sessions needed than PDT alone. This may be due to enhanced delivery of ALA from pre-treating the skin with non-ablative fractional photothermolysis.

Trends in the diagnosis and clinical features of melanoma in situ (MIS) in US men and women: A prospective, observational study.

BACKGROUND: The incidence of melanoma in situ (MIS) is increasing, but little is known about its clinical and epidemiologic features. OBJECTIVE: We sought to determine trends in diagnosis and clinical features of MIS. METHODS: Incident cases of melanoma were collected prospectively from the Nurses' Health Study (1976-2010) and Health Professionals Follow-up Study (1986-2010). RESULTS: MIS incidence increased from 2 to 42 per 100,000 person-year among women, and from 11 to 73 per 100,000 person-year among men, exceeding the rate of increase of invasive melanomas. Melanoma mortality initially increased during the follow-up period then plateaued. Men were more likely than women to develop in situ melanomas on the upper half of the body (P < .001). Invasive melanomas were diagnosed at a younger age than MIS (P < .001), and were more likely to be found on the lower extremities than MIS (P < .001). LIMITATIONS: This is a strictly descriptive study without examination into mechanisms. CONCLUSION: We found epidemiologic and clinical differences for in situ and invasive melanomas, which support further examination into the variations in etiologic pathways. The lack of improvement in mortality despite the increase in detection of in situ relative to invasive lesions further highlights the need to improve invasive melanoma-specific clinical screening features.

Nestin depletion induces melanoma matrix metalloproteinases and invasion.

Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated the expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. The development of three-dimensional melanospheres that in vitro partially recapitulate noninvasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase and increased melanoma cell responsiveness to transforming growth factor-beta, both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.

The role of natural and UV-induced skin pigmentation on low-fluence IPL-induced side effects: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: The risk of adverse skin effects following light-based hair removal is greater in pigmented skin based on the theory of selective photothermolysis. Thus sunlight-induced pigment i.e., facultative pigmentation, increases the risk of adverse skin effects, perhaps disproportionately. The aim of this study was to evaluate the influence of constitutive and facultative skin pigmentation on low-fluence intense pulsed light (IPL)-induced adverse skin effects. STUDY DESIGN/MATERIALS AND METHODS: Twenty-one subjects with Fitzpatrick skin type II-IV were enrolled. Two buttock blocks were randomized to receive 0 or 8 solar simulated ultraviolet radiation (UVR) exposures of consecutively increasing Standard Erythema Doses (2-4 SED). Each block was subdivided into four sites, randomized to receive IPL of 0, 7, 8, or 10 J/cm(2) , once a week for 3 weeks. Biopsies were taken 16-24 hours after the first IPL exposure and subjects were seen 1 and 4 weeks after the last IPL exposure. Outcome measures were: (i) skin reactions, (ii) pain, (iii) mRNA expression of pigment-markers microphthalmia-associated transcription factor (MITF) and pro-opiomelanocortin (POMC), and (iv) clinical appearance of biopsy wounds. RESULTS: Skin pigmentation increased after UVR (baseline median 13.8%, after UVR 28.1%, P = 0.0001) in all skin types. Subjects reported low pain intensities (median 1.5, scale 0-10) and experienced transient erythema immediately after IPL exposure. No persistent erythema, blisters, crusting, textual, or pigment changes were observed. The risk of erythema and pain intensities increased with IPL dose and skin pigmentation (P < 0.03). There was no difference in pain or skin reactions in skin with similar degree of natural and facultative pigmentation (P ≥ 0.104). Expression of cellular pigment-markers was not influenced by IPL exposure, neither in constitutive nor in facultative pigmented skin. Clinical appearance of biopsy wounds was unaffected by IPL exposure. CONCLUSION: The prevalence and intensity of low-fluence IPL-induced adverse skin effects depended on IPL dose and skin pigmentation regardless of the origin, i.e., constitutive versus UV induced.

Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk.

ABCB5 is a multidrug resistance (MDR) member of the ATP-binding cassette (ABC) superfamily of active transporters and represents a marker for chemoresistant malignant melanoma-initiating cells. ABCB5 expression is closely linked to tumorigenicity and progression of diverse human malignancies, including melanoma, and is functionally required for tumor growth. Here, we genotyped 585 melanoma cases and 605 age-matched controls for 44 ABCB5 tagging single nucleotide polymorphisms (SNPs) to span a region covering 108.2kb of the gene on the 7p21.1 locus. We identified three SNPs that were associated with decreased melanoma risk in additive models: rs10231520 (OR: 0.83, 95% CI: 0.70-0.98), rs17817117 (OR: 0.82, 95% CI: 0.68-0.98), and rs2301641 (OR: 0.83, 95% CI: 0.69-0.98). Additionally, the rs2301641 SNP was associated with non-red compared to red hair color (OR: 0.38, 95% CI: 0.14-1.03) in controls. Twelve human melanoma cell lines were genotyped for the rs2301641 SNP, which encodes a non-synonymous ABCB5 amino acid change (K115E). Functional studies revealed that the E form associated with lower melanoma risk correlated significantly with decreased ABCB5 transport capacity (P<0.01) and increased melanin production (P<0.05). Our results identify novel associations of the ABCB5 K115E polymorphism with human pigmentation phenotype and melanoma risk and point to potential functional roles of ABCB5 in melanomagenesis. Moreover, they provide a first example that functional variation in a prospective cancer stem cell marker can be associated with disease risk for the corresponding malignancy.

Melanocyte biology and skin pigmentation.

Melanocytes are phenotypically prominent but histologically inconspicuous skin cells. They are responsible for the pigmentation of skin and hair, and thereby contribute to the appearance of skin and provide protection from damage by ultraviolet radiation. Pigmentation mutants in various species are highly informative about basic genetic and developmental pathways, and provide important clues to the processes of photoprotection, cancer predisposition and even human evolution. Skin is the most common site of cancer in humans. Continued understanding of melanocyte contributions to skin biology will hopefully provide new opportunities for the prevention and treatment of skin diseases.

Isolation of tumorigenic circulating melanoma cells.

Circulating tumor cells (CTC) have been identified in several human malignancies, including malignant melanoma. However, whether melanoma CTC are tumorigenic and cause metastatic progression is currently unknown. Here, we isolate for the first time viable tumorigenic melanoma CTC and demonstrate that this cell population is capable of metastasis formation in human-to-mouse xenotransplantation experiments. The presence of CTC among peripheral blood mononuclear cells (PBMC) of murine recipients of subcutaneous (s.c.) human melanoma xenografts could be detected based on mRNA expression for human GAPDH and/or ATP-binding cassette subfamily B member 5 (ABCB5), a marker of malignant melanoma-initiating cells previously shown to be associated with metastatic disease progression in human patients. ABCB5 expression could also be detected in PBMC preparations from human stage IV melanoma patients but not healthy controls. The detection of melanoma CTC in human-to-mouse s.c. tumor xenotransplantation models correlated significantly with pulmonary metastasis formation. Moreover, prospectively isolated CTC from murine recipients of s.c. melanoma xenografts were capable of primary tumor initiation and caused metastasis formation upon xenotransplantation to secondary murine NOD-scid IL2Rγ(null) recipients. Our results provide initial evidence that melanoma CTC are tumorigenic and demonstrate that CTC are capable of causing metastatic tumor progression. These findings suggest a need for CTC eradication to inhibit metastatic progression and provide a rationale for assessment of therapeutic responses of this tumorigenic cell population to promising emerging melanoma treatment modalities.

Cutaneous Melanoma-A Review in Detection, Staging, and Management.

Melanoma is an increasingly common cancer in the United States, although mortality has likely stabilized. Diagnosis relies on a skilled practitioner with the aid of dermoscopy and initial local surgical management is a mainstay of treatment. Recent changes in staging emphasize continued use of sentinel lymph node biopsy to aid in prognostication although routine complete lymph node dissection has fallen out of favor. Advances in systemic treatment options, including targeted and immunotherapy, have dramatically changed the treatment paradigm for advanced melanoma and improved outcome. Prevention via sun protection remains a critical tool in efforts to limit the burden of this disease.

Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma.

Vitamin D deficiency (≤20 ng/mL) is associated with an increased incidence and worse prognosis of various types of cancer including melanoma. A retrospective, single-center study of individuals diagnosed with melanoma from January 2007 through June 2013 who had a vitamin D (25(OH)D3) level measured within one year of diagnosis was performed to determine whether vitamin D deficiency and repletion are associated with melanoma outcome. A total of 409 individuals diagnosed with histopathology-confirmed melanoma who had an ever measured serum 25(OH)D3 level were identified. 252 individuals with a 25(OH)D3 level recorded within one year after diagnosis were included in the study and the individual and melanoma characteristics such as age, sex, Breslow thickness, ulceration, stage, mitotic rate, and LDH were obtained from the medical record. A worse melanoma prognosis was associated with vitamin D deficiency (P=0.012), higher stage (P<0.001), ulceration (P=0.001), and higher mitotic rate (P=0.001) (HR 1.93, 95% CI 1.15-3.22). In patients with stage IV metastatic melanoma, vitamin D deficiency was associated with significantly worse melanoma-specific mortality (adjusted HR 2.06, 95% CI 1.10-3.87). Patients with metastatic melanoma who were initially vitamin D deficient and subsequently had a decrease or ≤20 ng/mL increase in their 25(OH)D3 concentration had significantly worse outcomes (HR 4.68, 95% CI 1.05-20.88) compared to non-deficient patients who had a >20 ng/mL increase. Our results suggest that initial vitamin D deficiency and insufficient repletion is associated with a worse prognosis in patients with metastatic melanoma.

Decreased tumor-infiltrating lymphocytes in nodular melanomas compared with matched superficial spreading melanomas.

Melanoma causes over 9000 deaths annually in the USA. Among its subtypes, nodular melanoma leads to a disproportionate number of fatalities compared with superficial spreading melanoma, the most common subtype. Recent breakthroughs in melanoma research have indicated a strong connection between melanoma virulence and the immune system. We hypothesize that the aggression of nodular melanoma may, in part, be because of decreased recognition by the immune system, as represented by a decreased presence of tumor-infiltrating lymphocytes (TILs), compared with its superficial spreading counterpart. Indeed, TILs on a primary melanoma have been used as a marker for immune response and have prognostic value for survival and sentinel lymph node status. After matching melanoma cases by age, sex, and Breslow thickness, we found significantly fewer TILs in nodular melanomas than in superficial spreading melanomas. This association was prominent in thin (≤2 mm) melanomas and was no longer significant in thick (>2 mm) melanomas. In addition, this difference in TILs was only present in men and not in women. Our finding suggests that nodular melanomas are more frequently associated with absent TILs, providing an avenue for further investigation into differences in immunogenicity of the primary melanoma and whether they underlie the unique virulence of nodular melanoma.

Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential.

Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening antitumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity, and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely dysplastic nevi, as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAM(KD)) or ST6GalNAc2-overexpressing (ST6(O/E)) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAM(KD) or ST6(O/E) melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1/melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy.