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Background: Photodynamic therapy (PDT) with topical δ-Aminolevulinic acid (ALA) has efficacy in treating basal cell carcinoma (BCC) but is limited by incomplete penetration of ALA into the deeper dermis. This prospective open-label pilot trial investigated the safety and efficacy of photosensitizer jet injection for PDT (JI-PDT) for BCC treatment. It was performed with 15 patients (n = 15) with histologically confirmed, untreated, low-risk nodular BCCs at a single institution., Methods: For the intervention, JI-PDT patients (n = 11) received two sessions of jet-injected ALA with PDT separated by four to 6 weeks. To further understand treatment technique, another group of patients (n = 4) received jet-injected ALA followed by tumor excision and fluorescence microscopy (JI-E). Treatment tolerability was assessed by local skin responses (LSR) score at five distinct time intervals. Fluorescence microscopy assessed protoporphyrin IX penetration depth and biodistribution within the tumor. At the primary endpoint, tumor clearance was evaluated via visual inspection, dermoscopy and reflectance confocal microscopy. Postinjection and postillumination pain levels, and patient satisfaction, were scored on a 0-10 scale., Results: Fifteen participants with mean age of 58.3, who were 15/15 White, non-Hispanic enrolled. The median composite LSR score immediately after JI-PDT was 5 (interquartile range [IQR] = 3) which decreased to 0.5 (IQR = 1) at primary endpoint (p < 0.01). Immunofluorescence of excised BCC tumors with jet-injected ALA showed photosensitizer penetration into papillary and reticular dermis. Of the 13 JI-PDT tumors, 11 had tumor clearance confirmed, 1 recurred, and 1 was lost to follow-up. 1/11 patients experienced a serious adverse event of cellulitis. 70% of patients had local scarring at 3 months. Patients reported an average pain level of 5.6 (standard deviation [SD] = 2.3) during jet injection and 3.7 (SD = 1.8) during light illumination., Conclusions: Jet injection of ALA for PDT treatment of nodular low-risk BCC is tolerable and feasible and may represent a novel modality to improve PDT., (© 2024 Wiley Periodicals LLC.)

Background: Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins., Objective: To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared with the gold standard histopathology., Methods: Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue, and histopathology was correlated with RCM results., Results: Seventy-two patients were included. Mean age was 66.8 years (standard deviation, 11.1; range, 38-89); 69.4% were men. Seventy of 72 lesions (97.2%) were located on the head and neck with mean largest clinical diameter of 1.3 cm (range, 0.3-5). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared with histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (κ = 0.71; P < .001)., Limitations: No RCM imaging beyond initial planned margins was performed., Conclusion: RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Squamous cell carcinoma in situ (SCCIS) of the nail unit is a complex malignancy; with little understanding of rate of upstaging or occult invasion in these patients. We sought to evaluate the rate of upstaging in nail unit SCCIS after Mohs micrographic surgery (MMS). Retrospective review of 346 patients who referred for and underwent MMS for biopsy proven SCCIS on the hands and feet between January 1, 2000 and December 30, 2019. Only cases in the nail unit were included. Clinical, surgical details, histopathological features, HPV status, and rate of upstaging were recorded. Thirty-one cases met the inclusion criteria and were analyzed. Twenty-four patients were males (77.4%). The mean age was 55 years (SD 17.26, range 27-84). The mean clinical size was 9.9 mm; 19 cases tested for HPV, 15/19 were positive (78.9%), and 8/19 (42.1%) were associated with high-risk HPV. Three patients (9.7%) were upstaged to invasive on either MMS margins or tumor debulking. Limitations included a relatively small sample size and retrospective in nature. The rate of upstaging of SCCIS in the nail unit is not frequent, and when upstaging occurred it was focal, superficial, and with no PNI or bone invasion., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Basal cell carcinoma (BCC) is the most common skin cancer, with over 2 million cases diagnosed annually in the United States. Conventionally, BCC is diagnosed by naked eye examination and dermoscopy. Suspicious lesions are either removed or biopsied for histopathological confirmation, thus lowering the specificity of noninvasive BCC diagnosis. Recently, reflectance confocal microscopy, a noninvasive diagnostic technique that can image skin lesions at cellular level resolution, has shown to improve specificity in BCC diagnosis and reduced the number needed to biopsy by 2-3 times. In this study, we developed and evaluated a deep learning-based artificial intelligence model to automatically detect BCC in reflectance confocal microscopy images. The proposed model achieved an area under the curve for the receiver operator characteristic curve of 89.7% (stack level) and 88.3% (lesion level), a performance on par with that of reflectance confocal microscopy experts. Furthermore, the model achieved an area under the curve of 86.1% on a held-out test set from international collaborators, demonstrating the reproducibility and generalizability of the proposed automated diagnostic approach. These results provide a clear indication that the clinical deployment of decision support systems for the detection of BCC in reflectance confocal microscopy images has the potential for optimizing the evaluation and diagnosis of patients with skin cancer., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Radiation therapy (RT) is a treatment option for select skin cancers. The histologic effects of RT on normal skin or skin cancers are not well characterized. Dermoscopy, high-frequency ultrasonography (HFUS), and reflectance confocal microscopy (RCM) are noninvasive imaging modalities that may help characterize RT response., Objectives: To describe changes in the tumor and surrounding skin of patients with basal cell carcinoma (BCC) treated with RT., Methods: The study was conducted between 2014 and 2018. Patients with biopsy-proven BCCs were treated with 42 Gy in 6 fractions using a commercially available brachytherapy device. Dermoscopy, HFUS, and RCM were performed before treatment and at 6 weeks, 3 months, and 12 months after RT., Results: A total of 137 imaging assessments (RCM + dermoscopy + HFUS) were performed in 12 patients. BCC-specific features were present in 81.8%, 91%, and 17% of patients imaged with dermoscopy, RCM, and HFUS at baseline, respectively, before treatment. After treatment, the resolution of these features was noted in 33.4%, 91.7%, and 100% of patients imaged with the respective modalities. No recurrences were seen after a mean of 31.7 months of follow-up., Limitations: Small sample size and no histopathologic correlation., Conclusion: Dermoscopy and HFUS were not as reliable as RCM at characterizing BCC RT response., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: There are no well-defined clinical factors to predict the risk of occult invasion in melanoma of the lentigo maligna type (LM) before complete histopathologic analysis., Objective: To evaluate whether clinical size was a predictor of invasion in LM and subclinical extension., Methods: Consecutive cases of LM were recorded in a prospectively maintained database from 2006 to 2019. Patient and tumor data were recorded during initial evaluation. The LM clinical area was calculated in square millimeters (length × width). All patients were treated with staged excision., Results: We included 600 patients. The mean age was 65.9 years (standard deviation, 12.3; range, 27-95 years); 62.8% (n = 377) were men. The mean LM clinical area was 128.32 mm 2 for in situ lesions versus 200.14 mm for invasive lesions (P = .1). Based on quantile regression, the median margin required for complete removal increased with LM clinical area., Limitations: The study was performed in a tertiary cancer center with possible referral bias and more complex cases., Conclusions: LM can present with variable clinical size, which may correlate with subclinical extension; however, the presence of invasion is not well estimated by LM clinical area., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool., Objective: To evaluate the treatment of EMPD patients and the role of RCM., Methods: Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded., Results: Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0-3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01)., Limitations: Relatively small sample size., Conclusion: Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of EMPD., (Copyright © 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Recently, a combined reflectance confocal microscopy (RCM)-optical coherence tomography (OCT) has been tested for the diagnosis of basal cell carcinoma (BCC). Evaluating the role of RCM-OCT in management of complex BCCs has not been studied. The objective of the study was to investigate the utility of a new combined RCM-OCT device in the evaluation and management of complex BCCs in a descriptive study., Methods: Prospective study of consecutive cases (July 2018-June 2019) of biopsy-proven 'complex' BCC defined as BCC in the head-and-neck area with multiple high-risk criteria such as large size in the mask area, multiple recurrences, and high-risk subtype. All cases were evaluated with a combined RCM-OCT device that provided simultaneous image viewing on a screen. Lesions were evaluated bedside with RCM-OCT according to previously described criteria., Results: Ten patients with complex head-and-neck BCCs had mean age of 73.1 ± 13.0 years. Six (60%) patients were males. Mean BCC clinical size was 1.9 ± 1.2 cm (range 0.6-4.0 cm). RCM detected residual BCC in 8 out of 10 cases (80%) and OCT detected residual BCC in all 10 cases (100%). Six BCCs (60%) had a depth estimate of > 1000 µm under OCT. In five cases, (50%) RCM-OCT imaging results led to a change/modification in BCC management., Conclusion: The use of a combined RCM-OCT device may help in the evaluation of complex head-and-neck BCCs by guiding treatment selection and defining the extent of surgery.

We investigated the utility of the fluorescent dye Deep Red Anthraquinone 5 (DRAQ5) for digital staining of optically sectioned skin in comparison to acridine orange (AO). Eight fresh-frozen thawed Mohs discard tissue specimens were stained with AO and DRAQ5, and imaged using an ex vivo confocal microscope at three wavelengths (488 nm and 638 nm for fluorescence, 785 nm for reflectance). Images were overlaid (AO + Reflectance, DRAQ5 + Reflectance), digitally stained, and evaluated by three investigators for perceived image quality (PIQ) and histopathological feature identification. In addition to nuclear staining, AO seemed to stain dermal fibers in a subset of cases in digitally stained images, while DRAQ5 staining was more specific to nuclei. Blinded evaluation showed substantial agreement, favoring DRAQ5 for PIQ (82%, Cl 75%-90%, Gwet's AC 0.74) and for visualization of histopathological features in (81%, Cl 73%-89%, Gwet's AC 0.67), supporting its use in digital staining of multimodal confocal micrographs of skin., (© 2020 Wiley-VCH GmbH.)

Background: There is lack of uniformity in the reflectance confocal microscopy (RCM) terminology for melanocytic lesions., Objective: To review published RCM terms for melanocytic lesions and identify redundant, synonymous terms., Methods: A systematic review of original research articles adhering to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was conducted until August 15, 2018. Two investigators gathered all published RCM terms used to describe melanoma and melanocytic nevi. Synonymous terms were grouped based on similarity in definition and in histopathologic correlation., Results: Out of 156 full-text screened articles, 59 studies met the inclusion criteria. We identified 209 terms; 191 (91.4%) corresponding to high-magnification/cellular-level terms and 18 (8.6%) corresponding to low-magnification/architectural patterns terms. The overall average use frequency of RCM terms was 3.1 times (range, 1-31). By grouping of individual RCM terms based on likely synonymous definitions and by eliminating terms lacking clear definition, the total number of RCM terms could be potentially reduced from 209 to 40 terms (80.8% reduction)., Limitations: Non-English and non-peer-reviewed articles were excluded., Conclusions: This systematic review of published RCM terms identified significant terminology redundancy. It provides the basis for subsequent terminology consensus on melanocytic neoplasms., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Accurate basal cell carcinoma (BCC) subtyping is requisite for appropriate management, but non-representative sampling occurs in 18% to 25% of biopsies. By enabling non-invasive diagnosis and more comprehensive sampling, integrated reflectance confocal microscopy-optical coherence tomography (RCM-OCT) may improve the accuracy of BCC subtyping and subsequent management. We evaluated RCM-OCT images and histopathology slides for the presence of two key features, angulation and small nests and cords, and calculated (a) sensitivity and specificity of these features, combined and individually, for identifying an infiltrative BCC subtype and (b) agreement across modalities., Methods: Thirty-three RCM-OCT-imaged, histopathologically-proven BCCs (17 superficial and/or nodular; 16 containing an infiltrative component) were evaluated., Results: The presence of angulation or small nests and cords was sufficient to identify infiltrative BCC on RCM-OCT with 100% sensitivity and 82% specificity, similar to histopathology (100% sensitivity, 88% specificity, kappa = 0.82). When both features were present, the sensitivity for identifying infiltrative BCC was 100% using either modality and specificity was 88% on RCM-OCT vs 94% on histopathology, indicating near-perfect agreement between non-invasive and invasive diagnostic modalities (kappa = 0.94)., Conclusions: RCM-OCT can non-invasively identify key histopathologic features of infiltrative BCC offering a possible alternative to traditional invasive biopsy., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We performed harmonized molecular and clinical analysis on 1,048 melanomas and discovered markedly different global genomic properties among subtypes (BRAF, (N)RAS, NF1, triple wild-type (TWT)), subtype-specific preferences for secondary driver genes and active mutational processes previously unreported in melanoma. Secondary driver genes significantly enriched in specific subtypes reflected preferential dysregulation of additional pathways, such as induction of transforming growth factor-β signaling in BRAF melanomas and inactivation of the SWI/SNF complex in (N)RAS melanomas, and select co-mutation patterns coordinated selective response to immune checkpoint blockade. We also defined the mutational landscape of TWT melanomas and revealed enrichment of DNA-repair-defect signatures in this subtype, which were associated with transcriptional downregulation of key DNA-repair genes, and may revive previously discarded or currently unconsidered therapeutic modalities for genomically stratified melanoma patient subsets. Broadly, harmonized meta-analysis of melanoma whole exomes revealed distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.

Background: Initial biopsy of basal cell carcinoma (BCC) may fail to show aggressive histologic subtypes. Additionality, the clinical evaluation of BCC before surgery can miss subclinical extension. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) are emerging tools that can help in the presurgical evaluation of BCCs., Objective: To assess the feasibility of a combined RCM-OCT imaging modality for presurgical evaluation of biopsy-proven BCCs for residual tumor, margin status, and depth., Methods: Thirty-eight BCCs in 35 patients referred to a tertiary cancer center for Mohs micrographic surgery (MMS) were imaged with combined RCM-OCT. Images were correlated to MMS frozen sections., Results: Thirty-eight BCCs were analyzed. The mean age of patients was 67.34 years (range, 36-84 years), and 20 patients were female (57.14%). Twenty four BCCs were located on the head (63.16%) , and the mean size was 8.58 mm (range, 3-30 mm). RCM-OCT showed an overall agreement of 91.1% with MMS frozen sections. A sensitivity of 82.6% (95% confidence interval [CI], 69%-92%), specificity of 93.8% (95% CI, 88%-97%), and receiver operating characteristic curve of 0.88 (95% CI, 0.82-0.94) was found. OCT depth was highly correlated with MMS depth (r 2 = 0.9)., Limitations: Small sample size and difficulty evaluating certain challenging anatomic sites., Conclusions: Combined RCM-OCT may emerge as a useful tool for presurgical evaluation of BCCs., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Basal cell carcinoma (BCC) treatment modalities can be stratified by tumor subtype and recurrence risk. The main limitation of nonsurgical treatment modalities is the lack of histopathologic confirmation. Reflectance confocal microscopy (RCM) is a noninvasive imaging device that provides quasihistologic images., Objective: To evaluate the feasibility and efficacy of RCM-guided carbon dioxide (CO 2 ) laser ablation of low-risk BCCs., Methods: Prospective study with biopsy specimen-proven low-risk BCCs imaged with RCM. RCM was performed on these sites before and after ablation. If residual tumor was found, a new series of laser passes were performed. The patients were then monitored for recurrence clinically and with RCM., Results: Twenty-two tumor sites in 9 patients (5 men, 4 women) were imaged and treated. Median age was 59 ± 12.9 years (range, 30-74 years). Mean tumor size was 7.7 mm (range, 5-10 mm). Residual tumor was identified in 5 of 22 cases (22.7%) under RCM on immediate first-pass postablation sites, prompting additional laser passes. Median follow-up was 28.5 months (range, 22-32 months) with no recurrences found., Conclusions: Addition of RCM to laser ablation workflow can detect subclinical persistent tumor after initial ablation and may serve as an aid to increase the efficacy of laser ablation., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Biopsy specimens from patients with basal cell carcinoma (BCC) can present to surgery with no clinically residual tumor, complicating treatment decisions., Objective: To evaluate reflectance confocal microscopy (RCM) for the assessment of residual BCC following biopsy., Methods: Consecutive patients with biopsy-proven BCC and no clinical evidence of residual tumor who had been referred for Mohs micrographic surgery were included. Biopsy sites were imaged with a handheld RCM device. On the basis of RCM evaluation, cases were labeled RCM positive or RCM negative. Mohs micrographic surgery was performed in all cases; margins and 15-μm serial vertical sectioning were evaluated., Results: A total of 61 patients were included (mean age, 61.7 years [standard deviation, 12.2 years]; range, 37-87 years); 60.7% were women. The mean lesion size was 5.1 mm (range, 3-12 mm); 73.8% of patients were positive on RCM, and 68.9% had residual BCC on histopathologic examination. The rates of RCM sensitivity, specificity, positive predictive value, and negative predictive value were 92.8%, 68.4%, 86.6%, and 81.2%, respectively. Three cases of BCC (high-risk, infiltrative, and basosquamous) were missed with use of RCM. When high-risk subtypes were excluded (n = 5), sensitivity and negative predictive value were both 100%., Limitations: RCM can miss deep-seated residual tumor., Conclusion: RCM is a valuable tool for the evaluation of residual BCC following biopsy, with the potential to reduce unnecessary surgical procedures., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The present work was designed to investigate the effect of palladium nanoparticles (PdNPs) on human skin malignant melanoma (A375) cells, for example, induction of apoptosis, cytotoxicity, and DNA damage. Diseases resulting from dermal exposure may have a significant impact on human health. There is a little study that has been reported on the toxic potential of PdNPs on A375. Cytotoxic potential of PdNPs (0, 5, 10, 20, and 40  μ g/ml) was measured by tetrazolium bromide (MTT assay) and NRU assay in A375 cells. PdNPs elicited concentration and time-dependent cytotoxicity, and longer exposure period induced more cytotoxicity as measured by MTT and NRU assay. The molecular mechanisms of cytotoxicity through cell cycle arrest and apoptosis were investigated by AO (acridine orange)/EtBr (ethidium bromide) stain and flow cytometry. PdNPs not only inhibit proliferation of A375 cells in a dose- and time-dependent model but also induce apoptosis and cell cycle arrest at G2/M phase (before 12 h) and S phase (after 24 h). The induction of oxidative stress in A375 cells treated with above concentration PdNPs for 24 and 48 h increased ROS level; on the other hand, glutathione level was declined. Apoptosis and DNA damage was significantly increased after treatment of PdNPs. Considering all results, PdNPs showed cytotoxicity and genotoxic effect in A375 cells.

Stigmasterol (99.9% pure) was isolated from Azadirachta indica and its chemopreventive effect on 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer was investigated in Swiss albino mice. Skin tumors were induced by topical application of DMBA and promoted by croton oil. To assess the chemopreventive potential of stigmasterol, it was orally administered at a concentration of 200 mg/kg and 400 mg/kg three times weekly for 16 weeks. Reduction in tumor size and cumulative number of papillomas were seen as a result of treatment with stigmasterol. The average latency period was significantly increased as compared with the carcinogen-treated control. Stigmasterol induced a significant decrease in the activity of serum enzymes, such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin as compared with the control. Stigmasterol significantly increased glutathione, superoxide dismutase, and catalase as compared with the control. Elevated levels of lipid peroxide and DNA damage in the control group were significantly inhibited by administration of stigmasterol. From the present study, it can be inferred that stigmasterol has chemopreventive activity in an experimental model of cancer. This chemopreventive activity may be linked to the oxidative stress of stigmasterol. The antigenotoxic properties of stigmasterol are also likely to contribute to its chemopreventive action.

Extensive applications of cerium oxide (CeO2) nanoparticles require a better understanding of their possible effects on human health. However, data demonstrating the effect of CeO2 nanoparticles on the human skin melanoma cell remain scanty. In the current study, we determined the mechanism through which CeO2 nanoparticles (APS <25 nm) induce toxicity in human skin melanoma cells (A375). The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and neutral red uptake assays showed concentration and time-dependent cytotoxicity of CeO2 nanoparticles in A375 cells. CeO2 nanoparticles significantly induced the generation reactive oxygen species (ROS) and malondialdehyde, superoxide dismutase, and decreased glutathione levels in A375 cells. It was also observed that the CeO2 nanoparticles induced chromosomal condensation and caspase-3 activity. CeO2 nanoparticles exposed cells revealed the formation of DNA double-strand breakage as measured by percent tail DNA and olive tail moment through comet assay. The decline of cell viability, production of ROS, and DNA damage in A375 cells specifies that CeO2 nanoparticles have less capable to induce cyto and genotoxicity.

The prevalence of metastatic basal cell carcinoma (MBCC) varies between 0.0028% and 0.55% of all cases. In total, more than 300 MBCC have been reported in the literature. We report the case of a 72 year old lady, who presented in September 2009 with a 10-year history of a progressively growing, giant, facial basal cell carcinoma (BCC). Clinical and imaging evaluations identified large local invasion with bone and meningeal involvement. Treatment consisted of an extensive surgery including left eye exenteration and meningeal resection followed by radiotherapy. A solitary lung metastasis was identified five months after the primary tumor resection. As the lesion remained solitary but had increased in size five months later, the patient finally accepted a surgical resection. A right upper-lobe pneumonectomy was performed and pathologic examination confirmed the metastasis as a MBCC.