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Background and Objectives The literature supporting Mohs micrographic surgery and staged excision in treating primary cutaneous melanoma is growing but has not been critically reviewed for bias. Methods Articles concerning Mohs micrographic surgery and staged excision for melanoma were assessed using modified “Risk of Bias in Non-randomized Studies of Interventions” (ROBINS-I) criteria, which measures bias in 7 categories. Results Forty-seven of 48 (97.9%) studies reviewed had serious or critical bias. None were randomized controlled trials. The most frequent cause of critical bias was poorly defined outcomes. The least frequent form of bias observed was change in intervention. Limitations The modified ROBINS-I criteria cannot account for all study limitations. Modification of the criteria leads to some degree of subjectivity. Conclusion The current body of literature suffers from limitations due to serious or critical bias in 1 or more ROBINS-I criteria. Local recurrence rate definitions are often poorly defined or not defined at all. Longer follow-up times, clear tumor classifications, and prospective, randomized study designs are necessary to improve the quality of future research.

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 to 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 (SD 11.1; 38 – 89 years); 69.4% were males. 70/72 (97.2%) lesions were located on the head neck with mean largest clinical diameter of 1.3cm (0.3 – 5 cm). 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 to the histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (kappa 0.71; p 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.

To provide patient-centered care, it is essential to explore what patients consider important and to adjust care accordingly. This may specifically be relevant for patients with complex skin cancer, for whom the care process is often more complicated and psychological and social problems may play a larger role. The objective was to explore the experiences and needs of patients who had undergone surgical treatment by a dermatologist for a complex skin cancer with a subsequent reconstruction by a plastic surgeon. An interview study was conducted among 16 patients who had undergone surgical treatment by a dermatologist and reconstruction by a plastic surgeon for basal cell carcinoma, cutaneous squamous cell carcinoma, or lentigo maligna. The interviews focused on patients’ experiences and needs regarding care using a predefined topic list. All interviews were audio-taped, transcribed verbatim and inductively analyzed using Atlas.ti. Patients reported a need for a skilled and friendly physician who tailors information and communication to their individual situation. A need for continuity of care and improved collaboration between healthcare providers was also emphasized. Furthermore, patients experienced complications and unmet expectations and expressed a need for shared decision-making at various steps throughout the treatment process (depending on age). Patients also considered completeness of tumor removal, follow-up visits with multiple specialists to be planned the same day and recognition of the psychological impact of the disease on the partner important. To improve patient-centered care for complex skin cancer patients, more efforts should be directed towards improving continuity of care and collaboration. Furthermore, it is advocated for physicians to be sensitive to the individual needs of patients and their partner and adjust information, communication and (supportive) care accordingly.

Resumen: El melanoma desmoplásico (MD) representa entre el 0,4-4% de todos los melanomas. Se presenta como un tumor constituido predominantemente por melanocitos fusiformes amelanóticos inmersos en un estroma colágeno abundante. Se clasifica en MD puro o mixto, basándose en la proporción de melanoma desmoplásico frente a la del melanoma no desmoplásico presente en el tumor infiltrante. En el MD puro el componente desmoplásico representa más del 90% del melanoma infiltrante mientras que, en el MD combinado o mixto, el componente desmoplásico representa menos del 90%.El MD es más frecuente en varones (ratio 1,7-2:1); la edad media al diagnóstico oscila entre 66-69 años y suele localizarse en áreas de fotoexposición crónica, a menudo asociado a un lentigo maligno. Su reconocimiento clínico es difícil ya que se presenta como una pápula o placa no pigmentada, indurada y de bordes mal definidos, que recuerda a una cicatriz.El MD es un tumor con una alta tendencia a la recurrencia local y en el caso del MD puro, una baja tendencia a la diseminación ganglionar. Sin embargo, en las series más contemporáneas, su pronóstico global parece ser similar al de melanomas no desmoplásicos (MND) del mismo grosor. Su abordaje clínico posee algunos matices diferenciales, en comparación al resto de melanomas, que se revisan en el presente trabajo. Abstract: Desmoplastic melanoma (DM) accounts for 0.4% to 4% of all melanomas. These skin tumors are mainly formed by amelanotic spindled melanocytes immersed in an abundant collagen stroma and are classified as pure when the desmoplastic component accounts for at least 90% of the invasive tumor and as mixed or combined otherwise. DMs are more common in men (male to female ratio, 1.7 to 2:1), and the mean age at diagnosis is 66 to 69 years. The tumors tend to occur in chronically sun-exposed areas, often in association with lentigo maligna, and are difficult to recognize because they can resemble a scar, presenting as a firm, unpigmented papule or plaque with poorly defined borders. DMs also have a strong tendency to recur locally, and pure variants rarely spread to the lymph nodes. Nonetheless, recently published series suggest that patients with DM have a similar prognosis to those with nondesmoplastic melanoma of the same thickness. The clinical management of DM varies in certain aspects from that of other melanomas and is reviewed in this article.

Introducción: El Melanoma es una neoplasia que se origina de los melanocitos. Este tumor, a pesar de representar solo el 5% de las neoplasias cutáneas, es el responsable del 70% de las muertes producidas por cáncer de piel. En Colombia se ha registrado una supervivencia del 79% a 5 años y en el caso particular del melanoma lentiginoso acral de tan solo 54%. No obstante, los datos nacionales no son claros, por lo cual es necesario caracterizar los pacientes con dicho diagnóstico para contribuir con futuros estudios. Metodología: Estudio de corte transversal en el cual se incluyeron y analizaron registros clínicos, demográficos e histopatológicos de pacientes con diagnóstico de melanoma cutáneo atendidos en dos instituciones de Bogotá, Colombia, durante los años 2012-2016. Resultados: Se incluyeron un total de 255 pacientes, la mayoría mujeres (61%). Se observó un aumento de 22 a 64 casos diagnosticados en los años 2012 y 2016 respectivamente. El subtipo histológico más frecuente fue el lentigo maligno (27.8%) seguido del melanoma lentiginoso acral (17.6%). La principal localización fue la cara (43.1%). El tiempo entre la detección y la confirmación del diagnóstico por biopsia fue de 17 meses. El 59.2% de los casos correspondió con un índice de Breslow

Background Mohs micrographic surgery (MMS) has risen in popularity as a management option for treating lentigo maligna (LM) because of its ability to accurately detect subclinical spread while conserving tissue. The primary concern for opponents of MMS in melanoma remains the difficulty associated with interpretation of frozen sections compared with traditional paraffin sections; this has been made easier with the advent of immunostaining. Objective Our study aims to assess the concordance in clearance reporting of LM in immunostained frozen sections compared with permanent paraffin sections and hematoxylin and eosin staining. Methods We conducted a retrospective analysis of 38 LM cases treated by MMS between 2017 and 2020 in Melbourne, Australia. Immunostained frozen sections were assessed by a Mohs surgeon, whereas permanent paraffin sections were assessed by an external dermatopathologist. Results We report 86% agreement in reporting of LM in immunostained frozen sections compared with permanent paraffin sections. In 5/38 cases, permanent paraffin sections were reported as clear for LM, but the Mohs surgeon had detected positive margins, requiring further excision. Conclusion For LM treated with MMS, there is a high agreement of clearance reporting between immunostained stained frozen sections and permanent paraffin sections without immunostaining; however, immunostained frozen sections may be more sensitive.

Background Fluorescence-advanced videodermatoscopy (FAV) is a new non-invasive high-resolution skin imaging technique to assess pigmented lesions in conjunction with the clinical examination and dermatoscopy. Objectives This is the first prospective study to identify morphologic descriptors and standardized terminology to examine facial pigmented lesions using FAV. The objectives were to identify FAV indicators, which can assist physicians in diagnosing suspicious flat facial pigmented lesions. Methods Consecutive equivocal pigmented lesions were retrospective analysed. Histopathological examination was performed for all the lesions. The main cytomorphological and cytoarchitectural FAV features were described and correlated with histopathological characteristics. Results From January to October 2020, 21 consecutive clinically suspected pigmented lesions in 20 patients were analysed using dermatoscopy and FAV and then surgically excised. Histopathological examination identified lentigo maligna (LM), lentigo maligna melanoma (LMM), solar lentigo (SL), flat seborrheic keratosis (SK) and pigmented actinic keratosis (PAK). Thirteen malignant melanocytic lesions were removed (11 LM, 2 LMM), two were diagnosed as PAK, and the remaining six pigmented lesions were SL-SKs. With FAV, large ovoid pleomorphic and dendritic cells arranged in the intrafollicular disposition, are typical of most malignant melanocytic lesions (12/13, 92.3%). No benign lesions displayed these features. In dermatoscopy, this folliculotropism corresponded to the presence of an annular-granular pattern with slate grey dots that were aggregated asymmetrically around follicular openings. Conclusions FAV features can provide an improved diagnostic approach in the differential diagnosis of flat pigmented facial lesions.

Lentigo maligna (LM) is a common in situ melanoma subtype arising on chronically sun-damaged skin and mostly affects the head and neck region. Localisation in cosmetically sensitive areas, difficulty to obtain wide resection margins and advanced patient age/comorbidities have encouraged investigation of less invasive therapeutic strategies than surgery in managing complex cases of LM. Radiotherapy and imiquimod have emerged as alternative treatment options in this context. The treatment of LM with imiquimod cream can be challenging due to the nature of the disease including its often large size, variegated appearance, involvement of adnexal structures, poorly defined peripheral edge and frequent localisation close to sensitive structures such as the eyes and lips, and elderly patients with multiple comorbidities. Prolonged and unpredictable inflammatory reaction and side effects and compliance with a patient-delivered therapy can also be challenging. In the literature to date, studies evaluating the use of imiquimod to treat LM have utilised varying methodologies and provided short follow-up and these limitations have impaired the development of clear guidelines for dosage and management of side effects. Based on our multidisciplinary experience and review of the literature, we propose practical clinical strategies for the use of imiquimod for treating LM, detailing optimal administration procedures in various clinical scenarios and long-term management, with the aim of facilitating optimal patient outcomes.

BACKGROUND Imiquimod cream may be used as a non-surgical treatment for lentigo maligna or as adjuvant therapy following excision to decrease the risk of recurrence. OBJECTIVES To evaluate histologic and clinical factors associated with clinical clearance of lentigo maligna treated with imiquimod. METHODS We performed a retrospective review of all patients diagnosed with lentigo maligna and treated with imiquimod between 1997 and 2019 at our academic institution. RESULTS We observed clinical clearance in 93% (66/71) of participants who received adjuvant imiquimod following surgery and 79% (19/24) in the primary non-surgical treatment group over a median of 38 months of follow-up. In the adjuvant therapy group, positive surgical margins were associated with a decreased rate of clinical clearance when compared to cases with close (

Prostaglandin F2a analogs (PGAs) are considered efficacious in the first-line treatment of glaucoma. They have however been associated with a number of periocular side effects. We present a case of periocular hyperpigmentation and progression to lentigo maligna melanoma (LMM) in a patient using bimatoprost eye drops. We conducted a literature review regarding the etiology and pathophysiology of periocular pigmentation in this setting. A 71-year-old female Caucasian patient with open-angle glaucoma using bimatoprost exclusively in her right eye noticed an ipsilateral lower eyelid/upper cheek area dark lesion after commencing treatment. Examination demonstrated a heterogeneously pigmented lesion. Excisional biopsy demonstrated extensive lentigo maligna (melanoma in situ) with superficially invasive malignant melanoma in the lesion center. The patient underwent successful staged excision and reconstruction. Literature review has demonstrated case reports supporting periocular hyperpigmentation; however, there has been no description of progression to periocular lentigo maligna and melanoma in a patient using bimatoprost.

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 mm2 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.

The infiltration of tissue-resident memory (T RM) cells in melanoma correlates with improved survival, suggesting an important role for T RMcells in immunity against melanoma. However, little is known about the presence of T RMcells in nonmalignant and premalignant melanocytic lesions. This study aimed to evaluate the presence of T RMcells in human skin melanocytic lesions, representing the spectrum from healthy skin to metastatic melanoma. FFPE sections from healthy skin, sun-exposed skin, benign nevi, lentigo maligna (LM), primary LM melanoma, and primary cutaneous and metastatic melanoma were analyzed by immunohistochemistry. The number of infiltrating cells expressing T RM-associated markers, CD3, CD4, CD8, CD69, CD103, and CD49a, was quantified by digital analyses. Multiplex immunofluorescence was performed to analyze coexpression of T RMcell markers. More T cells and CD69 +cells were found in melanoma lesions, as compared with healthy skin and nevi. CD103 +and CD49a +cell numbers did not significantly differ. More importantly, no differences were seen in expression of all markers between healthy skin and benign nevi. Similar results, except for CD69, were observed in LM melanoma, as compared with LM and sun-exposed skin. Interestingly, multiplex immunofluorescence showed that nevi tissues have comparable CD103 +T cell numbers with healthy skin but comprise more CD103 +CD8 +cells. Expression of T RMcell markers is significantly increased in melanoma, as compared with nonmalignant skin. Our data also show that T RMcells are not abundantly present already in premalignant tissues. Further studies on the specificity of T RMcells for melanocyte/melanoma antigens may reveal their significance in cancer immunosurveillance.

S. Lim, School of Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia

Background The incidence of xeroderma pigmentosum (XP) in Yemen seems to be quite high but there are no previous reports. Objective To study the clinicoepidemiologic aspect of XP in Yemen. Methods All 40 patients (24 male and 16 female patients from 32 families) treated and followed between 1997 and 2014 were subjected to detailed analysis with the help of a standardized protocol. The diagnosis was based on clinical features and histopathologic data, when needed. The diagnosis of tumors was confirmed by histopathologic examination in all cases. Results The median age of onset of initial manifestations was 9.5 months, and that of malignant lesions was 7 years. Parents of the patients were not affected, but history of consanguinity was recorded in 38. Initial lesions, such as dryness of the skin and freckles on the face, were noticed in all patients. In addition, erythema of the face with photosensitivity was observed in 21 patients. Premalignant and malignant skin lesions observed later were actinic keratosis in 15 patients, lentigo maligna in one, squamous cell carcinoma (SCC) in 10, and basosquamous carcinoma in one. Eyes were affected with SCC in seven and malignant melanoma (MM) in two patients. SCC of the lip developed in two patients and that of the tongue in one patient. Judicious use of acitretin in 12 patients showed good result. Conclusion XP in Yemen is characterized by a relatively high incidence, high percentage of consanguinity in parents of the patients, early onset of initial manifestations, malignant tumors, and severe ocular and oral lesions. Acitretin showed good result.

The clinical differentiation of face and scalp lesions (FSLs) is challenging even for trained dermatologists. Studies comparing the diagnostic performance of a convolutional neural network (CNN) with dermatologists in FSL are lacking.A market-approved CNN (Moleanalyzer-Pro, FotoFinder Systems) was used for binary classifications of 100 dermoscopic images of FSL. The same lesions were used in a two-level reader study including 64 dermatologists (level I: dermoscopy only; level II: dermoscopy, clinical close-up images, textual information). Primary endpoints were the CNN's sensitivity and specificity in comparison with the dermatologists' management decisions in level II. Generalizability of the CNN results was tested by using four additional external data sets.The CNN's sensitivity, specificity and ROC AUC were 96.2% [87.0%-98.9%], 68.8% [54.7%-80.1%] and 0.929 [0.880-0.978], respectively. In level II, the dermatologists' management decisions showed a mean sensitivity of 84.2% [82.2%-86.2%] and specificity of 69.4% [66.0%-72.8%]. When fixing the CNN's specificity at the dermatologists' mean specificity (69.4%), the CNN's sensitivity (96.2% [87.0%-98.9%]) was significantly higher than that of dermatologists (84.2% [82.2%-86.2%]; p 0.001). Dermatologists of all training levels were outperformed by the CNN (all p 0.001). In confirmation, the CNN's accuracy (83.0%) was significantly higher than dermatologists' accuracies in level II management decisions (all p 0.001). The CNN's performance was largely confirmed in three additional external data sets but particularly showed a reduced specificity in one Australian data set including FSL on severely sun-damaged skin.When applied as an assistant system, the CNN's higher sensitivity at an equivalent specificity may result in an improved early detection of face and scalp skin cancers.

Background A recently introduced dermoscopic method for the diagnosis of early lentigo maligna (LM) is based on the absence of prevalent patterns of pigmented actinic keratosis and solar lentigo/flat seborrheic keratosis. We term this the inverse approach. Objective To determine whether training on the inverse approach increases the diagnostic accuracy of readers compared to classic pattern analysis. Methods We used clinical and dermoscopic images of histopathologically diagnosed LMs, pigmented actinic keratoses, and solar lentigo/flat seborrheic keratoses. Participants in a dermoscopy masterclass classified the lesions at baseline and after training on pattern analysis and the inverse approach. We compared their diagnostic performance among the 3 timepoints and to that of a trained convolutional neural network. Results The mean sensitivity for LM without training was 51.5%; after training on pattern analysis, it increased to 56.7%; and after learning the inverse approach, it increased to 83.6%. The mean proportions of correct answers at the 3 timepoints were 62.1%, 65.5, and 78.5%. The percentages of readers outperforming the convolutional neural network were 6.4%, 15.4%, and 53.9%, respectively. Limitations The experimental setting and the inclusion of histopathologically diagnosed lesions only. Conclusions The inverse approach, added to the classic pattern analysis, significantly improves the sensitivity of human readers for early LM diagnosis.

Background: Melanoma has been described to have preferential left-sided laterality on the human body. The distribution and invasion patterns of lentigo maligna (LM) and lentigo maligna melanoma (LMM) have not been well described. Methods: This was a cross-sectional, retrospective study at a single, academic center. LM and LMM cases from 2008-2018 in the dermatopathology registry were analyzed. Results: A total of 392 cases were included (241 LM and 151 LMM). There was no laterality preference overall. The only exception were neoplasms located on the head/neck, which showed a left-sided laterality. LM and LMM had the highest incidence on the head/neck, followed by upper extremities, trunk, then lower extremities. Men had a higher incidence on the head/neck and trunk, while women had a higher incidence on the extremities. Interestingly, the upper extremities and the right side of the female body had a higher propensity for invasive lesions. Conclusion: While melanomas demonstrate preferential left-sided laterality, LM and LMM only share this pattern in respect to the head/neck region. Our results complement previous study findings which characterize LM and LMM as a head/neck and upper extremity pathology. Finally, our study suggests that certain body sites and laterality have an increased propensity for invasion.

Reflectance confocal microscopy (RCM) is a noninvasive imaging tool used for in vivo visualization of the skin. It has been extensively studied for use in the evaluation of equivocal cutaneous neoplasms to decrease the number of biopsy procedures in patients with benign lesions. Furthermore, its applications are broadening to include presurgical cancer margin mapping, tumor recurrence surveillance, monitoring of ablative and noninvasive therapies, and stratification of inflammatory disorders. With the approval of category I Current Procedural Terminology reimbursement codes for RCM image acquisition and interpretation, use of this technology has been increasingly adopted by dermatologists. The first article in this 2-part continuing medical education series highlights basic terminology, principles, clinical applications, limitations, and practical considerations in the clinical use of RCM technology.