Successful implementation of handheld reflectance confocal microscopy as the standard of care in the (surgical) management of lentigo maligna (melanoma).

BACKGROUND: Reflectance confocal microscopy (RCM) has shown promise in predicting surgical outcomes by non-invasively detecting subclinical lentigo maligna (melanoma) (LM/LMM). OBJECTIVES: To assess the effects of presurgical mapping using handheld RCM (HH-RCM) on surgical treatment, follow-up outcomes and management decisions. METHODS: A total of 117 consecutive LM/LMM cases (2015-2023) were included. The diagnostic accuracy of HH-RCM in detecting subclinical LM and invasive components was evaluated. The primary endpoints included histological margin status and changes in management based on the outcomes of the HH-RCM mapping procedure. Margin and follow-up outcomes were compared to a historical cohort before HH-RCM was introduced in our center (n = 94) (2003-2014). RESULTS: HH-RCM detected subclinical LM in 60% (n = 60) of cases. The median mapping duration was 14 min (range 4-50). In 27% (n = 33), the mapping procedure resulted in modified management, the majority consisting of limited surgery with adjuvant imiquimod (n = 15) or imiquimod monotherapy (n = 14). The remaining cases (n = 84) underwent HH-RCM-assisted surgery. Histological margins were cleared in 96.5% of the patients with a median histological margin of 3.0 mm, significantly higher than 81% in the historical cohort (median 2.0 mm) (p = 0.001). The sensitivity and specificity for detecting the extent of subclinical LM were 94% (95% CI 80.4-99.3) and 84% (95% CI 70.3-92.7), respectively. The negative predictive value for the detection of LMM was 94% (95% CI 84.4-97.7), and 75% of the initially missed LMM (n = 12) were identified during the HH-RCM mapping procedure. The study cohort had a 1.6% local recurrence rate compared with 25% in the historical cohort. CONCLUSIONS: Integrating HH-RCM as the standard of care could lead to more personalized treatment strategies for LM/LMM and allows for the selection of patients suitable for nonsurgical treatment.

Brain metastases in adult patients with melanoma of unknown primary in the Netherlands (2011-2020).

BACKGROUND: Although patients with melanoma of unknown primary (MUP) have a better prognosis than similar-staged melanoma patients with known primary, the occurrence of brain metastases (BM) entails a serious complication. This study provides an overview of the incidence, treatment patterns, and overall survival (OS) of adult patients with BM-MUP in the Netherlands. METHODS: BM-MUP cases were retrieved from the Netherlands Cancer Registry. Patient, disease and treatment-related characteristics were summarised using descriptive statistics. Overall survival (OS) was calculated by the Kaplan-Meier method, and the impact of prognostic factors on OS was assessed using Cox proportional hazard regression analyses. RESULTS: Among 1779 MUP patients, 450 were identified as BM-MUP (25.3%). Of these patients, 381 (84.7%) presented with BM along with other metastases, while 69 (15.3%) had BM only. BM-MUP patients were predominantly male (68.2%), and had a median age of 64 years at diagnosis (interquartile range 54-71 years). Over time, the proportion of BM along other metastatic sites increased, and the occurrence of BM decreased (p = 0.01). 1-Year OS improved for the total population, from 30.0% (95% confidence interval (CI): 19.8-40.9%) in 2011-2012 to 43.6% (95%CI: 34.5-52.3%) in 2019-2020, and median OS more than doubled from 4.2 months (95%CI: 3.3-6.2 months) to 9.8 months (95%CI: 7.0-13.2 months). Patient's age, localisation of BM, presence of synchronous liver metastasis and treatment were identified as independent predictors of OS. CONCLUSION: Notwithstanding the progress made in OS for patients with BM-MUP in the past decade, their overall prognosis remains poor, and further efforts are needed to improve outcomes.

Lentigo maligna (melanoma): A systematic review and meta-analysis on surgical techniques and presurgical mapping by reflectance confocal microscopy.

Because of an increased risk of local recurrence following surgical treatment of lentigo maligna (melanoma) (LM/LMM), the optimal surgical technique is still a matter of debate. We aimed to evaluate the effect of different surgical techniques and reflectance confocal microscopy (RCM) on local recurrence and survival outcomes. We searched MEDLINE, Embase and PubMed databases through 20 May 2022. Randomized and observational studies with ≥10 lesions were eligible for inclusion. Bias assessment was performed using the Methodological Index for Non-Randomized Studies instrument. Meta-analysis was performed for local recurrence, as there were insufficient events for the other clinical outcomes. We included 41 studies with 5059 LM and 1271 LMM. Surgical techniques included wide local excision (WLE) (n = 1355), staged excision (n = 2442) and Mohs' micrographic surgery (MMS) (n = 2909). Six studies included RCM. The guideline-recommended margin was insufficient in 21.6%-44.6% of LM/LMM. Local recurrence rate was lowest for patients treated by MMS combined with immunohistochemistry (<1%; 95% CI, 0.3%-1.9%), and highest for WLE (13%; 95% CI, 7.2%-21.6%). The mean follow-up varied from 27 to 63 months depending on surgical technique with moderate to high heterogeneity for MMS and WLE. Handheld-RCM decreased both the rate of positive histological margins (p < 0.0001) and necessary surgical stages (p < 0.0001). The majority of regional (17/25) and distant (34/43) recurrences occurred in patients treated by WLE. Melanoma-associated mortality was low (1.5%; 32/2107), and more patients died due to unrelated causes (6.7%; 107/1608). This systematic review shows a clear reduction in local recurrences using microscopically controlled surgical techniques over WLE. The use of HH-RCM showed a trend in the reduction in incomplete resections and local recurrences even when used with WLE. Due to selection bias, heterogeneity, low prevalence of stage III/IV disease and limited survival data, it was not possible to determine the effect of the different surgical techniques on survival outcomes.

The use of lasers in vitiligo, an overview.

Various types of lasers have been demonstrated to be effective in the treatment of vitiligo. The mode of action of these lasers is just as varied as the purpose of intervention. Many clinicians are not aware of the unique opportunity these lasers offer to improve the outcomes of vitiligo treatment. To date, no clear overview exists of the use of lasers in vitiligo treatment. Thus, the aim of this review is to discuss the various types of lasers and provide an overview of the evidence for their efficacy. We found good evidence from a systematic review that the excimer laser is effective, induces repigmentation rates comparable to NB-UVB and has improved outcomes when combined with calcineurin inhibitors. Ablative lasers are commonly used for tissue graft or melanocyte-keratinocyte cell graft transplantation. They provide safe, fast and uniform denudation of the epidermis with propitious repigmentation outcomes. We found conflicting evidence from two systematic reviews regarding the efficacy of fractional ablative lasers for improving outcomes of NB-UVB therapy, a systematic review including only fractional ablative lasers provided evidence for efficacy. Q-switched nanosecond lasers have shown to be safe and effective for inducing depigmentation, although recurrence is common, and most studies were small and retrospective. Despite proven efficacy and safety, laser treatments are relatively expensive and suited for limited body surface areas and selected cases. Each type of laser has benefits and risks associated and should, therefore, be individually chosen based on location, extent, activity and type of vitiligo.

Donor to recipient ratios in the surgical treatment of vitiligo and piebaldism: a systematic review.

Stabilized vitiligo resistant to conventional therapy (e.g. segmental vitiligo) and piebaldism lesions can be treated with autologous cellular grafting techniques, such as non-cultured cell suspension transplantation (NCST) and cultured melanocyte transplantation (CMT). These methods are preferred when treating larger surface areas due to the small amount of donor skin needed. However, the donor to recipient expansion ratios and outcomes reported in studies with cellular grafting vary widely, and to date, no overview or guideline exists on the optimal ratio. The aim of our study was to obtain an overview of the various expansion ratios used in cellular grafting and to identify whether expansion ratios affect repigmentation and colour match. We performed a systematic literature search in MEDLINE and EMBASE to review clinical studies that reported the expansion ratio and repigmentation after cellular grafting. We included 31 eligible clinical studies with 1591 patients in total. Our study provides an overview of various expansion ratios used in cellular grafting for vitiligo and piebaldism, which varied from 1:1 up to 1:100. We found expansion ratios between 1:1 and 1:10 for studies investigating NCST and from 1:20 to 1:100 in studies evaluating CMT. Pooled analyses of studies with the same expansion ratio and repigmentation thresholds showed that when using the lowest (1:3) expansion ratio, the proportion of lesions achieving >50% or >75% repigmentation after NCST was significantly better than when using the highest (1:10) expansion ratio (χ2 P = 0.000 and χ2 P = 0.006, respectively). Less than half of our included studies stated the colour match between different expansion ratios, and results were variable. In conclusion, the results of our study indicate that higher expansion ratios lead to lower repigmentation percentages after NCST treatment. This should be taken into consideration while determining which expansion ratio to use for treating a patient.

Validation of a Patient Global Assessment for extent, severity and impact to define the severity strata for the Self Assessment Vitiligo Extent Score (SA-VES).

BACKGROUND: The Self Assessment Vitiligo Extent Score (SA-VES) is a validated, patient-reported outcome measure to assess the body surface area affected with vitiligo. Information on how to translate the obtained score into extent, severity and impact strata (mild-moderate-severe) is still lacking. Stratification is helpful to define inclusion criteria for trials, enables comparison and pooling of trial results and can be used for epidemiological research. OBJECTIVES: The aim was to develop extent, severity and impact strata for the SA-VES based on validated anchor-based questions. METHODS: In total, 315 patients with vitiligo (non-segmental; age ≥ 16) recruited at the Ghent University Hospital (Belgium) completed a questionnaire that was conducted in cooperation with the Dutch Society for vitiligo patients to ensure content validity. First three anchor questions included in the questionnaire [Patient Global Assessment (PtGA) for vitiligo extent, severity and impact] were assessed for content validity, construct validity and intrarater reliability. Subsequently, the PtGAs were used to stratify the SA-VES based on ROC analysis. RESULTS: For all PtGAs (PtGA extent, PtGA severity, PtGA impact), at least 75% of hypotheses evaluated for construct validity were confirmed. Intrarater reliability of all PtGAs was good to excellent (ICCs PtGA extent: 0.623; PtGA severity: 0.828; PtGA impact: 0.851). The optimal cut-off values of the SA-VES between the three global categories (mild/limited - moderate - severe/extensive) were 1.05% and 6.45% based on PtGA extent, 2.07% and 4.8% based on PtGA severity and 2% and 3.35% based on PtGA impact. CONCLUSION: This study provides the first guide for the interpretation of the numerical output obtained by the SA-VES (vitiligo extent) and enables the translation into a global vitiligo grading for extent, severity and impact. As patients' interpretation of vitiligo extent, severity and impact may vary amongst patients worldwide, future international studies will be required.

Patients' perspective on current treatments and demand for novel treatments in vitiligo.

BACKGROUND: The treatment of non-segmental vitiligo (NSV) remains a challenge. Current treatments often achieve suboptimal clinical results. To improve these treatment results, several new therapies are being developed and investigated. There is, however, little evidence on the actual need for novel therapies. OBJECTIVE: To assess patients' perspective on current and novel therapies for vitiligo. METHODS: A prospective questionnaire study was conducted in a large cohort of vitiligo patients that consecutively visited the outpatient clinic of the Amsterdam University Medical Centre between April 2017 and January 2019. Patients were requested to fill in a digital questionnaire on patient characteristics, disease burden, quality of life, efficacy and satisfaction of current treatments and aspects regarding new treatments. RESULTS: A total of 325 vitiligo patients completed the questionnaire (60% response rate). Of the respondents, 94% believed that new and improved treatments are needed and 86% would be willing to participate in clinical trials investigating a new therapy. Sixty-nine per cent would agree on taking weekly injections if it led to effective treatment results. Of the patients that had received therapy before, 49% reported that the current treatments were not effective and 50% was not satisfied with the current treatments. Sixty-seven per cent of the patients experienced facial lesions as an extreme burden, whereas this was, 25%, 12% and 10% for lesions on the hands, trunk and feet, respectively. The emotional burden score was significantly higher in dark skin types compared with light skin types (respectively, 8 vs 5, U P < 0.05). CONCLUSION: There is a substantial need for new vitiligo therapies. A considerable number of patients in our study are dissatisfied with current treatments and are emotionally burdened by the disease. Moreover, the vast majority demands novel treatments and is willing to participate in clinical trials.

Ultraviolet photography in vitiligo: image quality, validity and reliability.

BACKGROUND: For clinical care and research in vitiligo, photographs with the use of ultraviolet (UV) light or Wood's lamp are often made. Conventional cameras are insensitive to UV light. The use of a UV camera (UV photography) might improve image quality and ameliorate the assessment of target lesions in vitiligo. OBJECTIVES: To determine image quality and the validity and reliability of UV photography for the assessment of vitiligo target lesions. METHODS: Images of patients with vitiligo were made with UV photography and a conventional camera, and lesions were drawn on graph paper and transparent sheets. Image quality was scored by vitiligo experts and medical interns. The intraclass correlation coefficients (ICCs) of the lesion size determined with UV photography combined with digital surface measurement and the other techniques were hypothesized to be above 0.6. The ICCs between UV images taken by the same physician and between two different physicians were calculated for determining inter- and intra-reliability. RESULTS: In total, 31 lesions of 17 patients were included. Image quality was assessed as good or very good for 100% and 26% for UV photography and the conventional camera, respectively. ICCs of UV photography and the conventional camera, drawing the lesions on transparent sheets and graph paper, were 0.984, 0.988 and 0.983, respectively, confirming our hypotheses. The ICCs of the intra-rater and inter-rater were 0.999 and 0.998, respectively. CONCLUSIONS: The results of this study indicate that the use of UV photography for the assessment of vitiligo lesions improves image quality and is valid and reliable.

Poor agreement between the automated risk assessment of a smartphone application for skin cancer detection and the rating by dermatologists.

BACKGROUND: Several smartphone applications (app) with an automated risk assessment claim to be able to detect skin cancer at an early stage. Various studies that have evaluated these apps showed mainly poor performance. However, all studies were done in patients and lesions were mainly selected by a specialist. OBJECTIVES: To investigate the performance of the automated risk assessment of an app by comparing its assessment to that of a dermatologist in lesions selected by the participants. METHODS: Participants of a National Skin Cancer Day were enrolled in a multicentre study. Skin lesions indicated by the participants were analysed by the automated risk assessment of the app prior to blinded rating by the dermatologist. The ratings of the automated risk assessment were compared to the assessment and diagnosis of the dermatologist. Due to the setting of the Skin Cancer Day, lesions were not verified by histopathology. RESULTS: We included 125 participants (199 lesions). The app was not able to analyse 90 cases (45%) of which nine BCC, four atypical naevi and one lentigo maligna. Thirty lesions (67%) with a high and 21 with a medium risk (70%) rating by the app were diagnosed as benign naevi or seborrhoeic keratoses. The interobserver agreement between the ratings of the automated risk assessment and the dermatologist was poor (weighted kappa = 0.02; 95% CI -0.08-0.12; P = 0.74). CONCLUSIONS: The rating of the automated risk assessment was poor. Further investigations about the diagnostic accuracy in real-life situations are needed to provide consumers with reliable information about this healthcare application.

Frequency and prognosis of associated malignancies in 504 patients with lymphomatoid papulosis.

BACKGROUND: Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. OBJECTIVE: To evaluate the frequency and prognostic significance of associated HM and non-HM in LyP patients. METHODS: In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. RESULTS: After a median follow-up of 120 months (range, 6-585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large-cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B-cell (n = 14) or myeloid origin (n = 5). Even after a 25-year follow-up period, percentages of associated HM did not exceed 20%. Thirty-nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow-up, after a median of 68 months (range of 3-286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin-limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4-3.3) for non-HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. CONCLUSIONS: An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring.

UV light set-ups for vitiligo photography, a comparative study on image quality and ease of use.

BACKGROUND: Ultraviolet (UV) light is an essential tool to assess the extent, spreading and staging of vitiligo. Different UV light set-ups are used for vitiligo photography, including the following: (i) hand-held Wood's lamps; (ii) soft boxes with UV lamps; (iii) UV flash attached to the camera; and (iv) high output UV flash. OBJECTIVE: Our objective was to compare UV light set-ups for vitiligo photography regarding image quality and ease of use. METHODS: Patients with vitiligo lesions with unclear borders were included. Two images were made with all four UV set-ups per patient, for a large and a small area. Image quality was scored separately by three blinded vitiligo experts on five criteria: overall quality, clearness of borders, contrast and sharpness and for larger areas the shadows. The two professional medical photographers were asked to score the ease of use for each set-up. RESULTS: A total of 88 photos were assessed from 11 patients. For larger areas, the frequency of a 'good' or 'very good' overall quality rating was 12.1% (Wood's), 6.1% (soft boxes), 15.2% (camera flash) and 78.8% (high output flash). For smaller areas, the score 'good' or 'very good' was given to 54.5%, 3%, 66.6% and 84.8% in the same order. For the shadow criteria, each set-up scored below 40% on a 'good' or 'very good' score. The high output flash was scored as most easy to use by the photographers. CONCLUSION: When comparing four different UV light set-ups for vitiligo photography, we concluded that the UV set-ups strongly influenced the quality scores of the obtained images. The high output flash scored best for both small and large areas and for ease of use. For small areas, Wood's lamp and camera flash were acceptable. All set-ups scored badly for shadows, and more research is needed to find the optimal exposure to avoid shadows.

A squamous cell carcinoma in a young woman with Lynch syndrome.

Lynch syndrome (LS) is an autosomal-dominant inherited disorder characterized by a predisposition to colorectal cancer and extracolonic cancers (particularly endometrium, ovary, stomach, small bowel, hepatobiliary tract, pancreas, urothelial tract, brain, and skin). Muir-Torre syndrome (MTS) is considered a phenotypical variant of LS, where patients develop sebaceous neoplasms and keratoacanthomas. Currently, only few studies and case reports suggest an association between LS and other skin cancers, such as Bowens' disease, melanoma and squamous cell carcinoma (SCC). In this case-report we describe the case of a 33-year-old woman with LS and a proven MSH2 germline mutation, presenting with a SCC on the right cheek. Immunohistochemistry lacked MSH2 and MSH6 protein staining. The tumor showed a discordance between immunohistochemistry and micro-satellite instability status, for which a clear explanation cannot be provided yet. To conclude whether this pattern is indicative for SCC occurring in LS patients, further analyses of other LS patients presenting with SCC should be carried out. Our patient's young age and skin type (Fitzpatrick phototype VI) suggest a possible link between LS and cutaneous SCC.