Molecular and Histopathological Characterization of Metastatic Cutaneous Squamous Cell Carcinomas: A Case-Control Study.

BACKGROUND: A subset of patients affected by cutaneous squamous cell carcinoma (cSCC) can exhibit locally invasive or metastatic tumors. Different staging classification systems are currently in use for cSCC. However, precise patient risk stratification has yet to be reached in clinical practice. The study aims to identify specific histological and molecular parameters characterizing metastatic cSCC. METHODS: Patients affected by metastatic and non-metastatic cSCC (controls) were included in the present study and matched for clinical and histological characteristics. Skin samples from primary tumors were revised for several histological parameters and also underwent gene expression profiling with a commercially available panel testing 770 different genes. RESULTS: In total, 48 subjects were enrolled in the study (24 cases, 24 controls); 67 genes were found to be differentially expressed between metastatic and non-metastatic cSCC. Most such genes were involved in immune regulation, skin integrity, angiogenesis, cell migration and proliferation. CONCLUSION: The combination of histological and molecular profiles of cSCCs allows the identification of features specific to metastatic cSCC, with potential implications for more precise patient risk stratification.

A rapidly growing nodule on the face during pregnancy.

It is well known that adnexal skin tumors can simulate other cutaneous neoplasia and that various types of benign and malignant skin tumors can develop or modify during pregnancy. Here, we report a case of trichoblastoma mimicking a keratoacanthoma arising in a nevus sebaceous during pregnancy. Given its unique clinical and dermoscopic features, this case highlights the pivotal role of clinicopathological correlation in the diagnosis of adnexal tumors with an atypical clinical presentation.

Dermatoscopy and reflectance confocal microscopy for basal cell carcinoma diagnosis and diagnosis prediction score: A prospective and multicenter study on 1005 lesions.

BACKGROUND: Basal cell carcinoma (BCC) is usually diagnosed by clinical and dermatoscopy examination, but diagnostic accuracy may be suboptimal. Reflectance confocal microscopy (RCM) imaging increases skin cancer diagnostic accuracy. OBJECTIVE: To evaluate additional benefit in diagnostic accuracy of handheld RCM in a prospective controlled clinical setting. METHODS: A prospective, multicenter study in 3 skin cancer reference centers in Italy enrolling consecutive lesions with clinical-dermatoscopic suspicion of BCC (ClinicalTrials.gov: NCT04789421). RESULTS: A total of 1005 lesions were included, of which 474 histopathologically confirmed versus 531 diagnosed by clinical-dermatoscopic-RCM correlation, confirmed with 2 years of follow-up. Specifically, 740 were confirmed BCCs. Sensitivity and specificity for dermatoscopy alone was 93.2% (95% CI, 91.2-94.9) and 51.7% (95% CI, 45.5-57.9); positive predictive value was 84.4 (95% CI, 81.7-86.8) and negative predictive value 73.3 (95% CI, 66.3-79.5). Adjunctive RCM reported higher rates: 97.8 (95% CI, 96.5-98.8) sensitivity and 86.8 (95% CI, 82.1-90.6) specificity, with positive predictive value of 95.4 (95% CI, 93.6-96.8) and negative predictive value 93.5 (95% CI, 89.7-96.2). LIMITATIONS: Study conducted in a single country. CONCLUSIONS: Adjunctive handheld RCM assessment of lesions clinically suspicious for BCC permits higher diagnostic accuracy with minimal false negative lesions.

Melanoma in children: A systematic review and individual patient meta-analysis.

The current evidence on paediatric melanoma is heterogeneous, especially regarding the prognosis of different histological subtypes. We sought to systematically review the evidence on paediatric melanoma, highlighting the major sources of heterogeneity and focusing on available data on single patients. A systematic search was performed from 1948 to 25 January 2021. Only studies reporting at least one case of cutaneous melanoma in patients aged ≤18 years were included. Unknown primary and uncertain malignant melanomas were excluded. Three couples of authors independently performed title/abstract screening and two different authors reviewed all the relevant full texts. The selected articles were manually cross-checked for overlapping data for qualitative synthesis. Subsequently data on single patients were extracted to perform a patient-level meta-analysis. PROSPERO registration number: CRD42021233248. The main outcomes were melanoma-specific survival (MSS) and progression-free survival (PFS) outcomes. Separate analyses were done of cases with complete information on histologic subtype, focusing on superficial spreading (SSM), nodular (NM) and spitzoid melanomas, as well as of those classified as de-novo (DNM) and acquired or congenital nevus-associated melanomas (NAM). The qualitative synthesis covered 266 studies; however, data on single patients were available from 213 studies including 1002 patients. Among histologic subtypes, NM had a lower MSS than both SSM and spitzoid melanoma, and a lower PFS than SSM. Spitzoid melanoma had a significantly higher progression risk than SSM and trended toward lower mortality. Focusing on nevus-associated status, DNM demonstrated better MSS after progression than congenital NAM, and no differences were highlighted in PFS. Our findings describe the existence of different biological patterns in paediatric melanoma. Specifically, spitzoid melanomas demonstrated intermediate behaviour between SSM and NM and showed a high risk of nodal progression but low mortality. This raises the question of whether spitzoid lesions are being over-diagnosed as melanoma in childhood.

Clinical Review of Mucosal Melanoma: The 11-Year Experience of a Referral Center.

INTRODUCTION: Mucosal melanoma is a rare neoplasm. Late diagnosis is caused by occult anatomic sites and scarcity of symptoms. Novel biological therapies have now become available. Demographic, therapeutical and survival records on mucosal melanoma are scarce. OBJECTIVES: To provide an 11-year retrospective clinical review of real-world data on mucosal melanomas managed in a tertiary referral center in Italy. METHODS: We included patients with histopathological mucosal melanoma diagnoses from January 2011 to December 2021. Data were collected until the last known follow-up or death. Survival analysis was performed. RESULTS: Among 33 patients, we found 9 sinonasal, 13 anorectal and 11 urogenital mucosal melanomas (median age 82, females 66.7%). Eighteen cases (54.5%) presented with metastasis (p<0.05). In the urogenital subgroup, only 4 patients (36.4%) had metastasis at diagnosis, all in regional lymph nodes. Sinonasal melanomas were surgically managed with a debulking procedure (44.4%); every case of anorectal and urogenital melanomas underwent radical surgery (30.8% and 45.5%). Fifteen patients were treated with biological therapy (p<0.05). Radiation therapy was used in all melanomas of the sinonasal region (p<0.05). Overall survival was longer for urogenital melanomas (26 months). Univariate analysis showed an increased hazard ratio for death in patients with metastasis. A negative prognostic value of metastatic status was reported by the multivariate model, while administration of first-line immunotherapy demonstrated a protective role. CONCLUSIONS: At diagnosis, the absence of metastatic disease is the most relevant factor that influences the survival of mucosal melanomas. Moreover, the use of immunotherapy might prolong the survival of metastatic mucosal melanoma patients.

Prevalence and clinical-pathological features of nevus-associated versus de novo melanoma: a retrospective cross-sectional study of 2806 cases.

Introduction: Nevus-associated melanoma (NAM) accounts for almost one third of all cutaneous melanomas; it is often associated with younger age, trunk location and lower Breslow's thickness compared to de novo melanoma (DNM). Objectives: To define the prevalence of NAM in a tertiary referral Center in Italy and to analyze its distribution according to demographics, clinical and histopathological variables. Methods: Data were retrospectively retrieved from the archive of the Pathology Unit from June 2011 to August 2020. NAMs were compared with DNMs according to demographic, clinical and histopathological variables. Results: A total of 2806 consecutive cases of melanoma were excised in 2537 patients. Of these, 431 (15.4%) were NAM. NAM patients were significantly younger than DNM patients (55.1±14.1 vs. 62.0±15.0 years, p<0.001); they were predominantly located on the trunk (64.0% vs. 47.9% of DNMs). Melanoma located on the head and neck, trunk and upper limbs respectively had 2.3 (95%CI:1.2-4.5, p:0.014), 3.2 (95%CI:2.1-5.1, p<0.001) and 3.5 (95%CI:2.0-6.1, p<0.001) more odds to be NAM than those on the lower limbs. Conclusions: Our results confirm the association of NAM with younger age and trunk location. We also demonstrated that body site differences of NAM distribution are enhanced before the sixth decade of life.

Effect of Reflectance Confocal Microscopy for Suspect Lesions on Diagnostic Accuracy in Melanoma: A Randomized Clinical Trial.

Importance: Previous systematic reviews and meta-analyses have concluded that given data paucity, a comparison of reflectance confocal microscopy (RCM) with dermoscopy is complex. They recommend comparative prospective studies in a real-world setting of suspect lesions. Objective: To test the hypothesis that RCM reduces unnecessary lesion excision by more than 30% and identifies all melanoma lesions thicker than 0.5 mm at baseline. Design, Setting, and Participants: This randomized clinical trial included 3165 patients enrolled from 3 dermatology referral centers in Italy between January 2017 and December 2019, with a mean (SD) follow-up of 9.6 (6.9) months (range, 1.9-37.0 months). The consecutive sample of 3165 suspect lesions determined through dermoscopy were eligible for inclusion (10 patients refused). Diagnostic analysis included 3078 patients (48 lost, 39 refused excision). Data were analyzed between April and September 2021. Interventions: Patients were randomly assigned 1:1 to standard therapeutic care (clinical and dermoscopy evaluation) with or without adjunctive RCM. Information available guided prospective clinical decision-making (excision or follow-up). Main Outcomes and Measures: Hypotheses were defined prior to study initiation. All lesions excised (baseline and follow-up) were registered, including histopathological diagnoses/no change at dermoscopy follow-up (with or without adjunctive RCM). Number needed to excise (total number of excised lesions/number of melanomas) and Breslow thickness of delayed diagnosed melanomas were calculated based on real-life, prospective, clinical decision-making. Results: Among the 3165 participants, 1608 (50.8%) were male, and mean (SD) age was 49.3 (14.9) years. When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs 33.3), lower benign to malignant ratio (3.7:1.0 vs 1.8:1.0), and a number needed to excise reduction of 43.4% (5.3 vs 3.0). All lesions (n = 15) with delayed melanoma diagnoses were thinner than 0.5 mm. Conclusions and Relevance: This randomized clinical trial shows that adjunctive use of RCM for suspect lesions reduces unnecessary excisions and assures the removal of aggressive melanomas at baseline in a real-life, clinical decision-making application for referral centers with RCM. Trial Registration: ClinicalTrials.gov Identifier: NCT04789421.

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.

Clinically unquestionable but histologically deceptive melanomas in acral skin grafts: PRAME confirms its role.

The aim of this study was to investigate the role of PRAME in reducing the risk of an underestimation of tumour margins, in a consecutive series of acral melanomas recurring on skin grafts.

Comparative Analysis of PRAME Expression in 127 Acral and Nail Melanocytic Lesions.

PRAME (PReferentially expressed Antigen in MElanoma), a cancer testis antigen expressed in low levels in gonadal, endometrial, and adrenal gland tissues, has been recently considered a valuable tool in the differential diagnosis between benign and malignant melanocytic lesions. The aim of the current study is to perform PRAME immunostaining on a large series of benign and malignant acral lesions to evaluate the reproducibility of data reported in the literature and to validate PRAME as an affordable tool in the differential diagnosis between benign and malignant acral melanocytic tumors. Immunohistochemical analysis for PRAME was performed in 127 benign and malignant acral and nail melanocytic lesions. To better correlate PRAME expression with the nature (benign vs. malignant) of the lesions, we categorized PRAME tumor cells percentage positivity and intensity in a cumulative score obtained by adding the quartile of positive tumor cells (0, 1+, 2+, 3+, 4+) to PRAME expression intensity in tumor cells (0, 1+, 2+, 3+). Adopting an arbitrary PRAME expression score of < 5 versus ≥5 resulted in a correct identification of 82.5% of benign and 87.1% of malignant lesions. PRAME immunohistochemistry demonstrated good sensitivity and specificity in the diagnosis of acral melanocytic lesions, however, in line with the previous literature, we identified a subset of challenging cases such as acral Spitz nevi, in situ melanomas, and small, thin, invasive melanomas in which PRAME did not correlate with morphologic features. This suggests that PRAME can be a valid tool to be incorporated in a diagnostic clinicopathologic algorithm, subject to morphologic characteristics.

Unusual dermoscopic patterns of basal cell carcinoma mimicking melanoma.

BACKGROUND: Basal cell carcinoma can simulate melanoma and specific dermoscopic criteria have not yet been defined in a large cohort. OBJECTIVE: To identify dermoscopic "trump" characteristics for differential diagnosis, identify cluster groups and assess the clinical impact of this study's findings. METHODS: Retrospective, multicentric comparative study of atypical, non-facial basal cell carcinoma (≥1 seven-point checklist criteria) and melanoma (with at least one BCC criteria) at dermoscopy. Observed dermoscopic features were used to develop a proposed score. Lesion clusters were defined with hierarchical analysis. Clinical impact was assessed with a blinded reader study following this study's results. RESULTS: A total of 146 basal cell carcinoma and 76 melanoma were included. Atypical vascular pattern was common to most lesions (74.5%). Twelve trump features were included in the proposed score (sensitivity 94.1% and specificity 79.5%). Cluster analysis identified 3 basal cell carcinoma and 3 melanoma clusters. Findings improved overall diagnostic accuracy and confidence (26.8% and 13.8%, respectively; p < 0.001). CONCLUSIONS: These findings support the notion that atypical vascular pattern should be considered a shared feature of both melanoma and atypical basal cell carcinoma. Our proposed score improves diagnostic accuracy and confidence. Absence of pigmented features was associated with lower diagnostic accuracy and confidence.

Evaluation of dermatoscopic criteria for early detection of squamous cell carcinoma arising on an actinic keratosis.

BACKGROUND: Advanced squamous cell carcinoma (SCC) can be discriminated easily from actinic keratosis (AK) based on clinical and dermatoscopic features. However, at the initial stage of dermal invasion, SCC might still be clinically flat and discrimination from AK remains challenging, even with the addition of dermatoscopy. OBJECTIVE: The aim of this study was to investigate the clinical and dermatoscopic criteria that could suggest early invasion and serve as potent predictors to discriminate early SCC from AK. METHODS: Clinical and dermatoscopic images of histopathologically diagnosed AKs and early SCCs were evaluated for the presence of predefined criteria by 3 independent investigators. RESULTS: A total of 50 early SCCs and 45 AKs were included. The main positive dermatoscopic predictors of early SCC were dotted/glomerular vessels (odds ratio [OR] 3.83), hairpin vessels (OR 12.12), and white structureless areas (OR 3.58), whereas background erythema represented a negative SCC predictor (OR 0.22). LIMITATIONS: The retrospective evaluation of images. Moreover, the differential diagnosis included in the study is restricted between AK and early SCC. CONCLUSIONS: We identified potent predictors for the discrimination of AK and early SCC that may better guide management decisions in everyday clinical practice.

Cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia: a systematic review of the literature.

The continuous improvement of life expectancy of patients with chronic lymphocytic leukemia (CLL) has resulted in increased risk of second primary malignancy that potentially may affect survival and quality of life of CLL patients. We performed a systematic review to assess the risk and the clinical-pathological features and prognosis of cutaneous squamous cell carcinoma (cSCC) in patients with CLL. We searched PubMed, Embase, and Cochrane Central Register of Control Trials databases for articles published from database inception to December 31, 2019. English-language studies reporting original data on patients with a specific diagnosis of CLL and cSCC were included. Data were extracted using a standardized extraction form, and any discordance was resolved by consensus. Descriptive data were generated by pooling patients from eligible studies. Of the 4588 non-duplicate records identified, 55 articles met our inclusion criteria. These studies reported that CLL patients have a 3.2% prevalence of cSCC, with an 11.5% cSCC-related lethality and an overall risk of metastasis of 5.7% (7.3% for regional lymph node involvement and 3.8% for distant metastasis). The quality of evidence was limited by the high heterogeneity in the design, populations, and objectives of the included studies. This systematic review suggests that cSCC in CLL patients tends to behave less aggressively compared with the solid organ transplant recipients but has a higher morbidity and mortality than in the general population. Future prospective studies are needed to increase the quality of evidence and to determine the best treatment modalities and screening intervals for these patients.

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.

New systemic therapies for cutaneous melanoma: why, who and what.

Incidence of melanoma has been increasing in both sexes in the last decades. Advanced melanoma has always been one of the deadliest cancers worldwide due to his high metastatic capacity. In the last ten years, progresses in the knowledge of the molecular mechanisms involved in the melanoma development and progression, and in immune-response against melanoma, empowered the development of two new classes of systemic therapeutic agents: target-therapies and immunotherapies. Both classes consist of monoclonal antibodies inhibiting specific molecules. Target-therapies are selectively directed against cells harboring the BRAFV600-mutation, while immunotherapies target the two molecules involved in immune-checkpoint regulation, enhancing the immune response against the tumor: cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 receptor (PD-1). Target- and immunotherapy demonstrated to improve both progression-free and overall survival in melanoma patients either in metastatic or in adjuvant settings. Several drugs have been approved in recent years as monotherapy or in combination, and many other drugs are currently under investigation in clinical trials. In the current review on new systemic therapies for cutaneous melanoma, we revised the molecular basis and the mechanisms of actions of both target- and immunotherapy (why). We discussed who are the best candidate to receive such therapies in both the adjuvant and metastatic setting (who) and which were the most important efficacy and safety data on these drugs (what).