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Summary: Background: Cutaneous immune‐related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). Objectives: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. Methods: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. Results: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous‐type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti‐CTLA4 was less frequent than anti‐programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01–0·76] and vitiligo (OR 0·07, 95% CI 0·006–0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02–0·31), lichenoid reactions (OR 0·15, 95% CI 0·03–0·77) and eczematous reactions (OR 0·24, 95% CI 0·07–0·78), all compared with pruritic rash. Conclusions: Our study showed that skin‐oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow‐up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic?Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work?In this multicentre cohort study we showed that ICI‐related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy.Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non‐small cell lung cancer.The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus.Clinical awareness and specialized dermatological consultation should be advocated. [ABSTRACT FROM AUTHOR]

Imiquimod monotherapy resulted in complete clinical response in 71-4% of treated patients, consistent with previous studies.3-5 These findings (and those of other studies) support surgery as the primary treatment for LM in operable patients, not only because of the higher cure rates, but also because it allows for complete histopathological evaluation and detection of possible microinvasion. Patient demographic characteristics and tumour baseline characteristics for each study group are shown in Table 1. Dear Editor, As lentigo maligna (LM) has a tendency for subclinical extension, staged excisions with margin control achieve lower recurrence rates than conventional wide local excision (0-9-5% vs. 8-20%).1,2 However, these surgical techniques are limited by the requirements of time, cost and training. [Extracted from the article]

Summary: Background: Frozen histological sections are used for intraoperative margin assessment during Mohs surgery. Fluorescence confocal microscopy (FCM) is a new tool that offers a promising and faster alternative to frozen histology. Objectives: To evaluate prospectively in a clinical setting the accuracy of FCM vs. frozen sections in margin assessment of basal cell carcinoma (BCC). Methods: Patients with BCC scheduled for Mohs surgery were prospectively enrolled. Freshly excised surgical specimens were examined by FCM and then frozen sections were evaluated. Permanent sections were obtained, in order to validate the sample technique. A blind re‐evaluation was also performed for discordant cases. Sensitivity and specificity levels, as well as positive and negative predictive values (PPV and NPV, respectively), were calculated and receiver–operating characteristic curves generated. Results: We enrolled 127 BCCs in as many patients (40·2% females). Seven hundred and fifty‐three sections were examined. All BCCs were located in the head and neck area. In evaluating the performance of FCM vs. frozen sections, sensitivity was 79·8%, specificity was 95·8%, PPV was 80·5% and NPV was 95·7% [area under the curve 0·88, 95% confidence interval 0·84–0·92 (P < 0·001)]. Forty‐nine discordant cases were re‐evaluated; 24 were false positive and 25 false negative. The performance of FCM and frozen sections was also evaluated according to the final histopathological assessment. Conclusions: We found high levels of accuracy for FCM vs. frozen section evaluation in intraoperative BCC margin assessment during Mohs surgery. Some technical issues prevent the wide use of this technique, but new devices promise to overcome these limitations. What's already known about this topic? Ex vivo fluorescent confocal microscopy (FCM) is a new imaging tool that offers an attractive alternative to conventional frozen histology for the detection of margins in freshly excised tissue. What does this study add? Our study of 753 specimens found that FCM is a valid imaging tool to assess basal cell carcinoma margins in Mohs surgery, with high diagnostic accuracy when compared with frozen sections.Furthermore, FCM is a safe procedure that result in few false‐negative cases when compared with permanent formalin‐embedded sections. Linked Comment: Notingher. Br J Dermatol 2019; 180:1295–1296. Respond to this article [ABSTRACT FROM AUTHOR]

The 2001 patients who enrolled in MSLT1 to contribute knowledge for future patients with melanoma deserve full publication of all undisclosed findings. There is a lack of adequate and appropriate reporting of key data from the Multicenter Selective Lymphadenectomy Trial 1 (MSLT1) of melanoma. SP d sp Percentages in the total patient columns are incomplete, missing outcomes for patients with thin melanoma. [Extracted from the article]

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Background A validated tool for the dynamic severity assessment of hidradenitis suppurativa/acne inversa ( HS) is lacking. Objectives To develop and validate a novel dynamic scoring system to assess the severity of HS. Methods A Delphi voting procedure was conducted among the members of the European Hidradenitis Suppurativa Foundation ( EHSF) to achieve consensus towards an initial HS Severity Score System ( HS4). Strengths and weaknesses of HS4 were examined by a multicentre prospective study. Multivariate logistic regression, discriminant analysis and receiver operating characteristic curves, as well as examination for correlation (Spearman's rho) and agreement (Cohen's kappa) with existing scores, were engaged to recognize the variables for a new International HS4 ( IHS4) that was established by a second Delphi round. Results Consensus HS4 was based on number of skin lesions, number of skin areas involved and Dermatology Life Quality Index ( DLQI), and was evaluated by a sample of 236 patients from 11 centres. Subsequently, a multivariate regression model calculated adjusted odds ratios for several clinical signs. Nodules, abscesses and draining tunnels resulted as the scoring variables. Three candidate scores were presented to the second Delphi round. The resulting IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe disease. Cohen's kappa was fair (κ = 0·32) compared with Hurley classification, and moderate (κ = 0·49) compared with Expert Opinion. Correlation was good (ρ > 0·6) with Hurley classification, Expert Opinion, Physician's Global Assessment and Modified Sartorius score, and moderate for DLQI (ρ = 0·36). Conclusions The novel IHS4 is a validated tool to dynamically assess HS severity and can be used both in real-life and the clinical trials setting. [ABSTRACT FROM AUTHOR]

Spitzoid lesions represent a challenging and controversial group of tumours, in terms of clinical recognition, biological behaviour and management strategies. Although Spitz naevi are considered benign tumours, their clinical and dermoscopic morphological overlap with spitzoid melanoma renders the management of spitzoid lesions particularly difficult. The controversy deepens because of the existence of tumours that cannot be safely histopathologically diagnosed as naevi or melanomas (atypical Spitz tumours). The dual objective of the present study was to provide an updated classification on dermoscopy of Spitz naevi, and management recommendations of spitzoid-looking lesions based on a consensus among experts in the field. After a detailed search of the literature for eligible studies, a data synthesis was performed from 15 studies on dermoscopy of Spitz naevi. Dermoscopically, Spitz naevi are typified by three main patterns: starburst pattern (51%), a pattern of regularly distributed dotted vessels (19%) and globular pattern with reticular depigmentation (17%). A consensus-based algorithm for the management of spitzoid lesions is proposed. According to it, dermoscopically asymmetric lesions with spitzoid features (both flat/raised and nodular) should be excised to rule out melanoma. Dermoscopically symmetric spitzoid nodules should also be excised or closely monitored, irrespective of age, to rule out atypical Spitz tumours. Dermoscopically symmetric, flat spitzoid lesions should be managed according to the age of the patient. Finally, the histopathological diagnosis of atypical Spitz tumour should warrant wide excision but not a sentinel lymph-node biopsy. [ABSTRACT FROM AUTHOR]

Background Dermoscopy is limited in differentiating accurately between pigmented lentigo maligna ( LM) and pigmented actinic keratosis ( PAK). This might be related to the fact that most studies have focused on pigmented criteria only, without considering additional recognizable features. Objectives To investigate the diagnostic accuracy of established dermoscopic criteria for pigmented LM and PAK, but including in the evaluation features previously associated with nonpigmented facial actinic keratosis. Methods Retrospectively enrolled cases of histopathologically diagnosed LM, PAK and solar lentigo/early seborrhoeic keratosis ( SL/ SK) were dermoscopically evaluated for the presence of predefined criteria. Univariate and multivariate regression analyses were performed and receiver operating characteristic curves were used. Results The study sample consisted of 70 LMs, 56 PAKs and 18 SL/ SKs. In a multivariate analysis, the most potent predictors of LM were grey rhomboids (sixfold increased probability of LM), nonevident follicles (fourfold) and intense pigmentation (twofold). In contrast, white circles, scales and red colour were significantly correlated with PAK, posing a 14-fold, eightfold and fourfold probability for PAK, respectively. The absence of evident follicles also represented a frequent LM criterion, characterizing 71% of LMs. Conclusions White and evident follicles, scales and red colour represent significant diagnostic clues for PAK. Conversely, intense pigmentation and grey rhomboidal lines appear highly suggestive of LM. [ABSTRACT FROM AUTHOR]

Background. Epidemiological and clinical data suggest that actinic damage to the skin is an important predictor of skin carcinogenesis. Aim. To investigate the association of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with sun-damage alterations seen by histopathology. Method. In the current prospective study, perilesional skin of SCC or BCC lesions was evaluated for presence of alterations associated with chronic photodamage. Presence of scarring, perineural/perivascular invasion, haemorrhage/haemorrhagic crust, ulceration/erosion and margin involvement were also assessed. Result. Of 6038 included lesions, 4523 (74.9%) were BCCs and 1515 (25.1%) were SCCs. Presence of actinic damage was five times more frequent in SCC than in BCC (OR = 5.29, 95% CI 4.44-6.00, P < 0.001), and diagnosis of SCC was twice as common in photo-exposed than nonphoto-exposed body sites (OR = 2.34, 95% CI 2.03-2.70, P < 0.001). There were twofold higher odds for actinic damage in SCC compared with Bowen disease (OR = 2.015, 95% CI 1.55-2.61, P < 0.001). Assessing the different BCC histological subtypes, we found that nodular BCC had at least twofold higher odds (OR = 2.63, 95% CI 2.09-3.32), infiltrative BCC had 48% higher odds (OR = 1.487, 95% CI 1.18-1.87) and basosquamous BCC had fourfold higher odds (OR = 4.10, 95% CI 3.01-5.57) of having actinic damage compared with superficial BCC. Conclusions. Histological verification of ultraviolet-associated alterations in the perilesional skin in patients with NMSC in our study confirms the aetiopathogenic link between sun exposure and epithelial carcinogenesis on a histopathological basis. This correlation was stronger for SCCs than for BCCs. [ABSTRACT FROM AUTHOR]

Background Dermoscopically, one of the most common findings in melanocytic lesions is a globular pattern. A regular globular pattern is a common finding in naevi. Melanoma can also show a globular pattern, with globules typically irregular in size, colour and distribution. Objectives To investigate the likelihood of diagnosing melanoma according to distinct dermoscopic and confocal aspects. Methods Dermoscopic and confocal aspects of 83 excised melanocytic lesions dermoscopically showing globules were analysed. Results Our study population included 39 acquired melanocytic naevi, 16 Spitz naevi and 28 melanomas. Univariate analysis showed that regular distribution of globules on dermoscopy is associated with a ninefold lower risk for melanoma, whereas an irregular distribution is associated with an almost 10-fold increased risk for melanoma. Concerning confocal features, dense nests are associated with a fivefold lower risk for melanoma, whereas loosely arranged nests are associated with an almost sixfold risk for melanoma; moreover, the presence of round cells is associated with a 17-fold lower risk for melanoma, whereas pleomorphic cells are associated with an almost 16-fold risk for melanoma. Conclusions So that melanoma is not missed, clinicians should carefully analyse globular lesions in adults, focusing, in particular, on the distribution of globules and on the presence of confocal cytological atypia. [ABSTRACT FROM AUTHOR]

Background The parallel ridge pattern ( PRP) is considered the dermoscopic hallmark of acral melanoma ( AM). However, it was recently shown that approximately one-third of AMs do not display a PRP dermoscopically, rendering their detection more troublesome. Objectives To investigate the diagnostic accuracy of dermoscopic criteria for the diagnosis of AM. Methods Dermoscopic images of consecutive cases of histopathologically diagnosed AMs and acral naevi with histopathological diagnosis or with at least 1 year of follow-up were evaluated by three independent investigators for the presence of predefined criteria. Crude and adjusted odds ratios and their corresponding 95% confidence intervals were calculated by univariate and multivariate logistic regression, respectively. Receiver operating characteristic curves were used to choose among competing classification schemes. Results In total 603 lesions (472 naevi and 131 AMs) were included in the study. A scoring system (named BRAAFF) composed of six variables was associated with optimal area under the curve and sensitivity for the diagnosis of AM. This method includes four positive (irregular blotches, ridge pattern, asymmetry of structures and asymmetry of colours) and two negative predictors (furrow pattern and fibrillar pattern). Conclusions The BRAAFF checklist significantly improves the diagnostic accuracy of dermoscopy for the diagnosis of AM. [ABSTRACT FROM AUTHOR]

Background Little is known about the variability of the dermoscopic criteria of squamous cell carcinoma ( SCC) according to the histopathological differentiation grade. Objectives To evaluate whether specific dermoscopic criteria can predict the diagnosis of poorly differentiated SCC compared with well- and moderately differentiated SCC. Methods Clinical and dermoscopic images of SCCs were retrospectively evaluated for the presence of predefined criteria. Univariate and adjusted odds ratios were calculated. Discriminant functions were used to plot receiver-operator characteristic curves. Results Of 143 SCCs included, 48 (33·5%) were well differentiated, 45 (31·5%) were moderately differentiated and 50 (35·0%) were poorly differentiated. Flat tumours had a fourfold increased probability of being poorly differentiated. Dermoscopically, the presence of a predominantly red colour posed a 13-fold possibility of poor differentiation, whereas a predominantly white and white-yellow colour decreased the odds of poorly differentiated SCC by 97% each. The presence of vessels in more than 50% of the tumour's surface, a diffuse distribution of vessels and bleeding were significantly associated with poor differentiation, while scale/keratin was a potent predictor of well- or moderately differentiated tumours. Conclusions Dermoscopy may be regarded as a reliable preoperative tool to distinguish poorly from well- and moderately differentiated SCC. Given that poor differentiation of SCC represents an independent risk factor for recurrence, metastasis and disease-specific death, identifying poorly differentiated tumours in vivo may enhance their appropriate management. [ABSTRACT FROM AUTHOR]

Background Applicability of dermoscopy in evaluation of outcome and monitoring of superficial basal cell carcinoma (s BCC) after nonablative therapies has not been sufficiently assessed. Objectives Certain dermoscopic criteria, namely pigmented structures, ulceration and arborizing vessels, have been suggested to predict the presence of residual disease [residual disease-associated dermoscopic criteria ( RDADC)]. We aimed to assess this hypothesis. Patients and methods Lesions exhibiting RDADC 3 months after treatment were biopsied and in the case of histopathological confirmation were excised. Lesions characterized by white/red structureless areas, superficial fine telangiectasias, or lacking any dermoscopic criterion, were monitored for 12 months. Results At the 3-month evaluation, one or more of the RDADC were detected in 25/98 (25·5%) s BCCs, in which histology confirmed tumour persistence. In 45 (61·6%) of the 73 remaining lesions, dermoscopy showed white/red structureless areas and/or superficial fine telangiectasias. Twenty-eight lacked any dermoscopic criterion of s BCC. The two latter groups entered follow-up. In total, disease recurred in 13 (17·8%) of the 73 lesions. Conclusions RDADC accurately predict residual disease. Absence of dermoscopic criteria of s BCC safely predicts complete histopathological clearance. Detection of white/red structureless areas and/or superficial fine telangiectasias warrants close monitoring to recognize early recurrence. [ABSTRACT FROM AUTHOR]

Background The presence of pigmentation might influence the management of basal cell carcinoma ( BCC), with pigmented BCC responding poorly to certain treatments. Clinical studies report on a generally lower frequency of pigmentation compared with dermoscopic and histopathological studies, but the true frequency at which pigmentation occurs in clinically nonpigmented BCC has not been studied in detail. Objectives To compare the clinical and dermoscopic frequency of pigmentation in a series of histopathologically diagnosed BCCs and to correlate it with patient demographics, tumour location and histopathological subtype. Methods Clinical and dermoscopic images of histopathologically confirmed BCCs were retrospectively evaluated for the presence of pigmentation. Dichotomous outcome variables were clinically pigmented and dermoscopically pigmented BCC. All separate dermoscopic variables were included in the analysis. Differences in proportions were evaluated using Pearson's chi-square test. Results Five hundred and seven BCCs from 507 patients with a mean age of 67 years and a male-to-female ratio of 1·35 : 1 were included in the study. Clinically, 295 tumours were judged as nonpigmented. Of those, dermoscopy disclosed pigmentation in 88 cases (29·8%). Overall, blue-grey ovoid nests were the most frequent dermoscopic pattern ( n = 184, 36·3%), followed by multiple blue-grey dots/globules ( n = 147, 29%) and maple-leaf-like areas ( n = 70, 13·8%). Superficial tumours exhibited mainly maple-leaf-like areas, spoke-wheel areas and brown dots, whereas pigmented nodular BCC was most frequently typified by the presence of blue-grey ovoid nests. Conclusions Dermoscopy allows detection of pigmentation in about 30% of clinically nonpigmented BCCs, providing additional information that may aid the clinical choice of adequate treatment modalities. [ABSTRACT FROM AUTHOR]

Background Dermoscopy is useful in evaluating skin tumours, but its applicability extends also to the field of inflammatory skin disorders. Plaque psoriasis (PP), dermatitis, lichen planus (LP) and pityriasis rosea (PR) are common inflammatory skin diseases, but little is currently known about their dermoscopic features. Objectives To determine and compare the dermoscopic patterns associated with PP, dermatitis, LP and PR and to assess the validity of certain dermoscopic criteria in the diagnosis of PP. Methods Patients with PP, dermatitis, LP and PR were prospectively enrolled. The single most recently developed lesion was examined dermoscopically and histopathologically. Variables included vascular morphology, vascular arrangement, background colour, scale colour, scale distribution and presence of Wickham striae. Univariate and adjusted odds ratios were calculated. Discriminant functions were used to plot receiver-operator characteristic curves. Results Eighty-three patients with PP and 86 patients with either dermatitis, LP or PR were included in the study. Dotted vessels in a regular arrangement over a light red background and white scales were highly predictive for the diagnosis of PP, whereas dermatitis more commonly showed yellow scales and dotted vessels in a patchy arrangement. PR was characterized by yellowish background, dotted vessels and peripheral scales; whitish lines (Wickham striae) were seen exclusively in LP. Conclusions PP, LP, PR and dermatitis show specific dermoscopic patterns that may aid their clinical diagnosis. Certain combinations of dermoscopic features can reliably predict the diagnosis of PP. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Use of Intravenous Bisphosphonates in Older Women With Breast Cancer," by S. H. Giordano et al. in the 2008 issue.