Advanced Cutaneous Squamous Cell Carcinoma: Italian Multicentric Retrospective Analysis of Patient Profiles and Therapeutic Approaches.

BACKGROUND: Advanced cutaneous squamous cell carcinoma (aCSCC) represents an area of unmet clinical need, with no standardized treatments until the recent approval of immune checkpoint inhibitors (ICIs). OBJECTIVES: The aim of the study was to describe clinical characteristics and therapeutic strategies of a real-life Italian cohort of aCSCC patients managed at the beginning of cemiplimab approval as compassionate use in Italy. METHODS: A multicenter retrospective study was performed by 10 Italian centers in the period January 1, 2018-May 31, 2020. Patients aged ≥18 years and diagnosed with aCSCC (locally aCSCC and metastatic CSCC) were eligible for the study. Analysis of patients' characteristics and treatment strategies was performed. RESULTS: 239 patients were initially recruited in the study: 19 patients were excluded due to incomplete data collection, yielding a final cohort of 220 patients, of which 191 and 220 were included for patients' clinical characteristics and therapeutic intervention analysis, respectively. Median age at the time of diagnosis was 81 years (range: 72-86); nodal metastases were detected in 64/220 (29%) patients, and distant metastatic spread was reported in 33/220 (15%) patients. Most of our patients referred chronic occupational and/or recreational sun exposure, experienced ≥1 sunburn during their lifetime, never wore hats or used photoprotective filters, and presented with signs of cumulative sun damage (solar lentigines and/or actinic keratosis). Majority of our cohort received at least one intervention directed to the primary tumor (n = 212, 96.3%); surgery and radiotherapy were the most common therapeutic choices. Immunotherapy was administered to a small number of patients as compassionate use, especially in the metastatic setting. CONCLUSIONS: Our study outlines the complex and heterogeneous clinical and therapeutic landscape of aCSCC patients at the beginning of ICI era, highlighting the need of a standardized care for this fragile and high-need patient population.

Is reflectance confocal microscopy useful in the differential diagnosis of extra facial lentigo maligna? A retrospective multicentric case-control study.

BACKGROUND: Extra facial lentigo maligna (EF-LM) arises outside the head and neck area. EF-LM presents the classic histological features of lentigo maligna. The dermoscopic aspects of EF-LM have been poorly studied. OBJECTIVE: The primary aims of our study were to analyse and describe the clinical, dermoscopic and confocal microscopy features of a series of histologically confirmed EF-LM. METHOD: We conducted a retrospective and multicentric study. From our database, we selected 48 cases of thin melanomas on photodamaged skin with histological features of EF-LM of which clinical, dermoscopic and confocal microscopy images were available, and a control group of 45 lesions, that can be subjected to differential diagnosis such as solar lentigo, lichenoid keratosis, seborrheic keratosis and melanocytic nevi, of which dermoscopic and confocal microscope images were available. RESULTS: Extra facial lentigo maligna had a higher prevalence of lentigo-like pigment patterns, angulated lines and zigzag structures. At confocal microscopy, LM-EF cases showed a higher prevalence of pagetoid spreading, round cells, dendritic cells in the epidermis, atypical cells at the dermo-epidermal junction, dendritic cells at the junction, meshwork pattern and elastosis. Our study shows that reflectance confocal microscopy (RCM) has a sensitivity of 90% and a specificity of 97% for the differential diagnosis of this type of melanoma. CONCLUSIONS: Extra facial lentigo maligna does not have the classic dermoscopic features of superficial spreading melanoma, the most observed dermoscopic criteria are angulated lines and lentigo-like pigment patterns without lentigo-like border. RCM can be a valuable imaging tool for the evaluation of all those suspicion skin lesions at dermoscopy highlighting cellular atypia suggestive for melanoma.

Characteristics and management of skin cancers in very elderly patients: A real-world challenge for clinicians.

The increase life expectancy led to an expected increase in skin cancer incidence in older patients. Their treatment can require a complex decision-making process. Limited data are available on characteristics, management and outcome of skin tumours in nonagenarian and centenarian patients. The aim of our study was to describe epidemiology, clinical-pathological features and treatment strategies of skin cancers in a cohort of patients aged ≧95 years. A total of 116 patients ≧95 years of age presented for the evaluation of 225 skin lesions (mean of 1.94 lesions per patient). The mean age was 97.4 years, 57.8% were women. Most patients had an ECOG score of 3 (49.3%) or 4 (32%). Lesions were mainly located on the head and neck area (74.2%), upper (7.1%) and lower (6,2%) limbs. The majority of patients presented with non-melanoma skin cancers (183/225; 81.3%), 25/225 (11.1%) had actinic keratosis, 5 (2.2%) melanoma and 2 (0.9%) atypical fibroxanthoma. Forty-eight lesions (21.3%) were treated with surgery, 58 (25.8%) with radiotherapy. The management of 73 lesion (32.4%) was discussed at the multidisciplinary tumour board meeting. One patient died for the progression of a squamous cell carcinoma; 74 patients died for causes unrelated to skin tumours, 36 are still alive after a mean follow-up of 27.27 months. This cohort study confirms that age is not per se a contraindication for treatment of skin cancers in elderly patients. Our results support the importance of a patient-centred care approach that should take into consideration patient's preferences, comorbidities, compliance and possible adverse events.

Neck Melanoma: Clinical, Dermoscopic and Confocal Features.

BACKGROUND: The head and neck are considered one single anatomical unit. No data on clinical, dermoscopic and confocal aspects of neck melanoma are currently available. OBJECTIVES: To identify clinical, dermoscopic and confocal diagnostic features of neck melanomas. METHODS: Consecutive malignant (cases) and benign (controls) melanocytic skin lesions located on the neck, excised as suspected of being melanoma from March 2011 to February 2018, were retrospectively retrieved. Dermoscopic criteria of the 7-point checklist, integrated by other melanoma features (such as grey colour and irregular hyperpigmented areas) were assessed. Reflectance confocal microscopy (RCM) images were examined when available. RESULTS: 282 lesions located to the head and neck area were biopsied to rule out melanoma. Thirty-one out of 282 (11%) lesions were located on the neck: 21 melanomas and 10 naevi. Melanoma patients were older than patients with naevi (mean age: 60.4 vs. 37.9 years, p < 0.001). Neck melanomas were more frequently located on sun-damaged skin compared to naevi (76.2 vs. 30%, p = 0.02). Dermoscopically, neck melanomas were characterized by irregular dots/globules, grey colour and regression (76.2, 81 and 46.7% of cases) and showed criteria of lentigo maligna melanoma (LMM) in 52.4% of cases. Regression, grey colour, irregular hyperpigmented areas and criteria of LMM typified melanomas on sun-damaged skin, whereas tumours located on non-sun-damaged areas were often characterized by irregular pigmentation (blotches). RCM, implemented to dermoscopy, correctly diagnosed 10/12 melanomas and 3/5 naevi. CONCLUSION: Neck melanoma has peculiar clinical and dermoscopic aspects that could help clinicians to distinguish it from naevi and to diagnose melanoma earlier.

Pigmented skin lesions displaying regression features: Dermoscopy and reflectance confocal microscopy criteria for diagnosis.

Melanomas and nevi displaying regression features can be difficult to differentiate. To describe reflectance confocal microscopy features in benign and malignant pigmented skin lesions characterized by regression features in dermoscopy. Observational retrospective study. Inclusion criteria were presence of dermoscopic features of regression; availability of clinical, dermoscopic and RCM imaging; definite histopathologic diagnosis. The study sample comprised 217 lesions; 108 (49.8%) melanomas and 109 were benign lesions, of which 102 (47.0%) nevi and 7 (3.2%) lichen planus-like keratosis (lplk). Patients with melanoma were significantly older than those with benign lesions (61.9 ± 15.4 vs 46.1 ± 14.8; P < 0.001) and a higher proportion of melanomas displayed dermoscopic regression structures in more than 50% of lesion surface (n = 83/108; 76.9%; P < 0.001). On RCM examination, pagetoid cells were significantly more reported in melanoma group, than in benign lesions (86.1% vs 59.6%; P < 0.001) and were more frequently widespread distributed (65.6% vs 20.0%; P < 0.001) and both dendritic and roundish (36.6% vs 15.4%; P < 0.001) in shape. Aspecific architecture at the dermo-epidermal junction (DEJ) was more commonly seen among melanomas than benign lesions (23.1% vs 11.9%; P = 0.002) with higher presence of dendritic and both dendritic and roundish atypical cells at the DEJ (28.7% vs 18.3% and 19.4% vs 3.7%; P < 0.001, respectively). Focal pagetoid infiltration and ringed or clod patterns were more commonly seen in benign lesion. In conclusion, the correct interpretation of regressing lesions remains a challenge, assessing carefully the extent and characteristics of architectural and cytologic atypia on RCM is an additional piece of the complex puzzle of melanoma diagnosis.

Dermoscopy of syringocystadenoma papilliferum.

Syringocystadenoma papilliferum is a benign adnexal neoplasm frequently seen in association with other adnexal tumours. We report the dermoscopic features of three cases of syringocystadenoma papilliferum developing in naevus sebaceus. Clinically the lesions were characterised by exophytic papillary structures. Dermoscopically, polymorphous vessels were the prevalent feature.

Dermoscopic Features of Basal Cell Carcinoma on the Lower Limbs: A Chameleon!

BACKGROUND: Lower limbs represent an uncommon location for basal cell carcinoma (BCC) and only few reports have described dermoscopic features of BCC in this body site. Since BCCs of the lower limbs frequently display nonclassic BCC dermoscopic criteria, they can simulate other benign or malignant lesions. OBJECTIVE: Our aim was to describe the dermoscopic features of BCC located on lower limbs and to define which criteria were more associated with their benign- or malignant-looking appearance. METHODS: We conducted a retrospective study enrolling consecutive patients with histologically confirmed BCCs of the lower limbs. Lesions were classified in 7 categories according to the clinical and dermoscopic global appearance. Clear BCC, squamous cell carcinoma (SCC) or Bowen disease-like, Kaposi disease-like, melanoma-like, and aspecific pattern were considered malignant-looking lesions; however, seborrheic keratosis-like and dermatofibroma-like were considered benign-looking. To define which dermoscopic criteria were independently associated with benign- or malignant-looking appearance, we conducted a multivariate logistic regression analysis. RESULTS: A total of 81 BCCs were enrolled: 18 (22%) were benign-looking lesions (of which 11 were seborrheic keratosis-like and 7 dermatofibroma-like) and 63 (78%) were malignant-looking BCCs (of which 24 were clear-cut BCCs, 23 SCC-like, 2 Kaposi disease-like, 9 melanoma-like, and 5 had aspecific pattern). Multivariate regression analysis showed that erosions/ulceration and vessels were independently associated with malignant-looking appearance. The most represented vessels were glomerular and polymorphic, which are more frequently encountered in SCC, together with ulceration. CONCLUSION: BCC of the lower legs frequently simulates other benign or malignant lesions, with SCC being the main differential diagnosis.

Orthovoltage radiotherapy for nonmelanoma skin cancer (NMSC): Comparison between 2 different schedules.

BACKGROUND: Radiotherapy is an established treatment for some types of patients with nonmelanoma skin cancer. A hypofractionated schedule has been proposed as a valuable option for elderly disabled patients to minimize the number of hospital visits. OBJECTIVE: We sought to compare a weekly hypofractionated orthovoltage radiotherapy regimen with a standard daily one for the treatment of nonmelanoma skin cancer. METHODS: A retrospective cohort study was performed on 436 tumors. Overall survival, disease-free survival, and cosmetic outcome were measured. Life-table analysis, Kaplan-Meier survival analysis, and multivariate Cox regression model were performed. RESULTS: The hypofractionated regimen was not associated with increased recurrence rates and mortality, or with a poorer cosmetic outcome, when compared with the daily schedule. LIMITATIONS: Absence of complete information about acute treatment toxicity and a shorter follow-up time for patients receiving the weekly schedule are limitations of this study. CONCLUSIONS: A weekly hypofractionated regimen of orthovoltage radiotherapy seems to be the most appropriate approach in elderly disabled patients with nonmelanoma skin cancers.

Efficacy and safety of systemic treatments for psoriasis in elderly patients.

Management of psoriasis in elderly patients can be challenging, because of the impairment of immune system efficiency and the presence of comorbidities that contra-indicate systemic therapies. We studied the safety and efficacy of systemic traditional and biological treatments in 187 consecutive psoriatic patients aged > 65 years. At week 12 of therapy, Psoriasis Area and Severity Index 75 was achieved by 49%, 27%, 46% and 31% of patients who received methotrexate, acitretin, cyclosporine or PUVA, and 64.1%, 64.7%, 93.3%, 57.1% and 100% of patients who received etanercept, adalimumab, infliximab, efalizumab and ustekinumab. The rate of adverse events was 0.12, 0.32, 1.4 and 0.5 per patient-year in the methotrexate, acitretin, cyclosporine and PUVA groups and 0.11, 0.35, 0.19, 0.3 and 0.26 in the etanercept, adalimumab, infliximab, efalizumab and ustekinumab groups. Traditional drugs were less effective than biologics in our elderly population. Etanercept was associated with a lower rate of adverse events compared with other treatments.

Negative pigment network identifies a peculiar melanoma subtype and represents a clue to melanoma diagnosis: a dermoscopic study of 401 melanomas.

The dermoscopic descriptor "negative pigment network" (NPN) has been reported in several types of melanocytic and non-melanocytic lesions, although it has a higher frequency of association with melanoma and Spitz naevus. In a study of 401 consecutive melanomas, excluding facial, acral and mucosal locations, the frequency and variability of NPN were investigated, and the results of NPN correlated with clinical and histopathological data. NPN of any extension was found in 27% of melanomas, most frequently invasive and arising from a naevus on the trunk of young subjects. Seven percent of melanomas in the study population showed presence of NPN in more than half of the lesion area; most of these did not show typical dermoscopic melanoma features. The authors propose a new melanoma subtype, in which extensive NPN should be considered as a diagnostic indicator.

Variegated dermoscopy of in situ melanoma.

BACKGROUND: Melanomas in situ (MIS) are difficult to diagnose, lacking well-established dermoscopic descriptors. OBJECTIVE: The aim of this study was to improve the identification of early melanomas describing the variegated dermoscopic features of MIS and their correlation with demographic and clinical aspects. METHODS: Dermoscopic images of 114 histologically proven MIS were evaluated by 3 expert dermoscopists and classified into their main dermoscopic patterns. Dermoscopic features were also considered for their correlation with clinical parameters. RESULTS: Eight different dermoscopic subtypes of MIS were identified: reticular grey-blue (27.2%), reticular (21.1%), multicomponent (20.2%), island (10.5%), spitzoid (7%), inverse network (6.1%), 'net-blue globules' (5.3%) and globular (2.6%). Clinical characteristics of lesions and patients varied according to the different dermoscopic groups. CONCLUSION: We hypothesize that the different dermoscopic subgroups of MIS correspond to lesions with a different origin and, possibly, various patterns of growth and a different biological behaviour.

Self-reported measure of subjective distress in response to COVID-19 pandemic in patients referred to our skin cancer unit during the first wave.

During the Italian first wave of the COVID-19 pandemic, social restrictions and bad news spread daily by mass media inevitably had a huge influence on the mental state of the population. To assess how much the COVID-19 outbreak impacted the psychologic state of patients referring to our Skin Cancer Unit from March 9 to May 31, 2020, we administered to them a self-report questionnaire, the Impact of Event Scale-Revised (IES-R). To evaluate the trend of the IES-R score over time, we set a temporal cutoff of March 27 (the day with the highest number of deaths for COVID-19 in Italy during the first wave). Three hundred fifty-five patients completed the questionnaire, reporting an average IES-R score of 25.5 (±16.4); 32.4% of participants reached a total IES-R score >32. Patients who visited after March 27, 2020 reported a higher psychologic impact, since the IES-R score significantly increased from 23.6 (±15.6) to 28.3 (±17.2). A group reported higher scores (of participants reaching an IES-R score >32, 57.4% were women and 33.9% were men). We gathered that, at an early stage of events of this magnitude, it could be useful to submit the IES-R questionnaire in high-risk and oncologic patients: we could potentially identify individuals at risk of developing post-traumatic stress disorders, who might be tempted to postpone necessary medical consultations. This could be also the basis for increasing targeted psychologic support in selected patients.

Quantitative evaluation of healthy epidermis by means of multiphoton microscopy and fluorescence lifetime imaging microscopy.

BACKGROUND/PURPOSE: Multiphoton microscopy (MPM) enables the assessment of unstained living biological tissue with submicron resolution, whereas fluorescence lifetime imaging microscopy (FLIM) generates image contrast between different states of tissue characterized by various fluorescence decay rates. The aim of this study was to compare the healthy skin of young individuals with that of older subjects, as well as to assess the skin at different body sites, by means of MPM and FLIM. METHODS: Nineteen elderly patients were examined on the outer side of the forearm, whereas 30 young individuals were assessed on the dorsal and volar sides of the forearm and on the thigh. RESULTS: Cell and nucleus diameters, cell density and FLIM vary according to the epidermal cell depth and the skin site. In elderly subjects, epidermal cells show morphologic alterations in shape and size, with smaller cell and nucleus diameters; the number of basal cells is decreased, whereas the mean fluorescence lifetimes at both the upper and the lower layers increase. CONCLUSION: This study provides quantitative and qualitative data on normal epidermis at different skin sites at different ages and represents a reference for the clinician attempting to understand the effectiveness of MPM and FLIM in discriminating diseased states of the skin from normal ones.

Clinical and Dermoscopic Factors for the Identification of Aggressive Histologic Subtypes of Basal Cell Carcinoma.

BACKGROUND: Infiltrative basal cell carcinoma (BCC) has a higher risk for post-surgical recurrence as compared to the most common low-aggressive superficial and nodular BCC. Independent diagnostic criteria for infiltrative BCC diagnosis have not been still defined. Improving the pre-surgical recognition of infiltrative BCC might significantly reduce the risk of incomplete excision and recurrence. OBJECTIVE: The aim of this study is to define clinical and dermoscopic criteria that can differentiate infiltrative BCC from the most common low-aggressive superficial and nodular BCC. METHODS: Clinical and dermoscopic images of infiltrative, superficial, and nodular BCC were retrospectively retrieved from our database and jointly evaluated by two experienced dermoscopists, blinded for the histologic subtype. Pairwise comparisons between the three histologic subtypes were performed and multivariable logistic regression models were constructed in order to define clinical and dermoscopic factors independently associated with each subtype. To validate our findings, two experienced dermoscopists not previously involved in the study were asked to evaluate clinical and dermoscopic images from an external dataset, guessing the proper BCC subtype between infiltrative, nodular and superficial, before and after being provided with the study results. RESULT: A total of 481 histopathologically proven BCCs (51.4% nodular, 33.9% superficial, and 14.8% infiltrative) were included. We found that infiltrative BCC mostly appeared on the head and neck as an amelanotic hypopigmented plaque or papule, displaying ulceration on dermoscopic examination, along with arborizing and fine superficial telangiectasia. Shiny white structures were also frequently observed. Multivariate regression analysis allowed us to define a clinical-dermoscopic profile of infiltrative BCC. CONCLUSIONS: We defined the clinical-dermoscopic profile of infiltrative BCC, allowing to differentiate this variant from superficial and nodular BCC. This will improve pre-surgical recognition of infiltrative forms, reducing the risk for post-surgical recurrence.