Similar local recurrence and survival in patients with T1 radial growth phase melanoma on head and neck treated with 5 or 10 mm margins: A retrospective study.

BACKGROUND: Melanoma guidelines recommend surgical excision with 10 mm margins for T1 melanomas (invasive melanomas with Breslow thickness ≤1 mm), including those in radial growth phase, which are without metastatic potential; however, such margins may be problematic on head-and-neck. OBJECTIVE: We compared outcomes of wide (10 mm margins) versus narrow (5 mm margins) excisions in patients with radial growth phase T1 melanoma on head-and-neck including face. METHODS: We retrospectively examined 610 consecutive patients excised with wide versus narrow margins, from 2001 to 2018, at six European centres. In all cases, radial growth phase, and clear margins with 5 or 10 mm of clearance, were ascertained histologically. Multivariable models investigated associations of margins and other factors with overall survival and local recurrence. RESULTS: Three hundred and sixteen (51.8%) patients received wide excision, 219 (69.3%) with primary wound closure, 97 (30.7%) with reconstruction; 294 (48.2%) patients received narrow excision, 264 (89.8%) with primary wound closure, 30 (10.2%) with reconstruction (p < 0.001). Median follow-ups were 88 months (wide) and 187 months (narrow) (inter-quartile ranges 43-133 and 79-206, respectively). Ten-year overall survival (95% confidence interval) was 96.7% (94.2%-99.3%) in wide and 98.2% (96.4%-100%) in narrow patients. Ten-year local recurrence incidence was 6.4% (4.1%-10.1%) in wide and 7.8% (5.3%-11.6%) in narrow groups. Lentigo maligna melanoma subtype appeared associated with increased risk of local recurrence in narrow versus wide patients (15.0% vs. 7.5%; p = 0.190). CONCLUSIONS: Narrower excision margins for T1 radial growth phase melanoma are not associated with worse overall survival (hazard ratio 0.97, p = 0.996) or increased local recurrence (subdistribution hazard ratio: 0.87; p = 0.751) compared to wider margins, and may be safely applied to such lesions, although caution may be required in the presence of lentigo maligna melanoma.

Long-term vemurafenib therapy in advanced melanoma patients: cutaneous toxicity and prognostic implications.

BACKGROUND: The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs). OBJECTIVES: To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders. METHODS: This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014. RESULTS: 62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors. CONCLUSIONS: Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

Neoplastic and inflammatory skin disorders and serum levels of polychlorinated biphenyls in a population living in a highly polluted area.

BACKGROUND: Although polychlorinated biphenyls (PCBs) have been classified as human carcinogens for their association with melanoma, few data are available for other skin lesions. OBJECTIVES: To investigate the prevalence of skin disorders in a highly PCB polluted area in northern Italy, with locally produced food as the main source of human contamination, and evaluate the association between skin lesions and PCB serum levels, taking account of possible confounders. MATERIALS & METHODS: Thirty-three PCB congeners were quantitatively assessed and a total of 189 subjects were equally divided into three groups using the tertiles of total PCB serum concentrations. All subjects underwent a clinical examination and were interviewed on their risk factors and history of skin diseases. RESULTS: No statistically significant difference was found in the prevalence of skin cancer, nevi, pigmentary disorders as well as inflammatory and infectious skin diseases among the three PCB exposure groups. It should be noted that the use of questionnaires to assess subjects' past sun exposure and photoprotection is intrinsically flawed due to random error. CONCLUSION: Our study does not support the hypothesis that chronic PCB exposure, through the ingestion of contaminated food, determines an increased risk of developing skin diseases.

Analysis of Sentinel Node Biopsy and Clinicopathologic Features as Prognostic Factors in Patients With Atypical Melanocytic Tumors.

BACKGROUND: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs. PATIENTS AND METHODS: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method. RESULTS: Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup. CONCLUSIONS: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor.

Factors Affecting Sentinel Node Metastasis in Thin (T1) Cutaneous Melanomas: Development and External Validation of a Predictive Nomogram.

PURPOSE: Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB. PATIENTS AND METHODS: The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram. RESULTS: Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines. CONCLUSION: We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.

Survey of cutaneous adverse reactions to targeted cancer therapies: value of dermatological advice.

BACKGROUND: Target-therapy offers a better efficacy for several cancers, with less toxic adverse effects, if compared with traditional chemotherapy. However cutaneous complications are increased in number and complexity. The severity of these reactions positively correlates with efficacy, and the management of these reactions is challenging. METHODS: This was a multicenter cross-sectional study on a consecutive series of adult patients with incident cutaneous reactions linked to targeted cancer therapies observed in five referral centers for cancer treatment in the province of Bergamo and Brescia in northern Italy. Each center was asked to collect data on the first 5 consecutive cases of severe adverse cutaneous events observed during a one-week surveillance period. RESULTS: From June to October 2012, 25 patients with cutaneous adverse reactions linked to targeted therapies were included in the study. The main prescribed drugs were cetuximab (52%) and erlotinib (20%) and the most common reactions were folliculitis/pustules (40%) and rash/erythema (40%). Hand-foot reaction syndrome was present in 8% of patients. A total of 30% of patients treated for a cutaneous reaction underwent a consultation by a dermatologist. In these patients the rate of oncologic therapy continuation without regimen modifications was higher (100%), while it was progressively lower in patients treated by oncologists (71%) or without any specific treatment (60%). CONCLUSIONS: Adverse reaction should be recognized by both dermatologists and oncologists and a multidisciplinary approach is mandatory.

Panniculitis and vitiligo occurring during BRAF and MEK inhibitors combination in advanced melanoma patients: Potential predictive role of treatment efficacy.

Panniculitis and vitiligo-like lesions have been recently identified as rare cutaneous side effects of the combination of BRAF and MEK inhibitors, a standard of care in metastatic and locally advanced BRAF V600 mutated melanoma. An immune-mediated mechanism has been advocated in the pathogenesis of these skin lesions. Herein we retrospectively reviewed our institutional experience with the aim to explore the association between the occurrence of panniculitis and vitiligo-like lesions during combination therapy with dabrafenib (D) and trametinib (T) and outcome of advanced melanoma patients. Among 52 consecutive BRAF V600 mutated melanoma patients submitted to DT in our center, 12 (23%) developed immune related skin lesions (IRSLs): 8 panniculitis and 4 vitiligo. Patients with IRSLs diagnosis obtained a better disease response (83% versus 25%) (p = 0.001) than their counterpart and had a longer progression free survival and overall survival. The association of IRSLs and lower risk of disease progression (HR 0.19; CI 95% 0.04-0.90; p = 0.043) was confirmed after adjusting for major prognostic factors in multivariate analysis. IRSLs might represent an easy predictive surrogate marker for treatment response and favourable outcome in melanoma patients submitted to DT combination therapy.

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

BACKGROUND: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. METHODS: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. FINDINGS: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. INTERPRETATION: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. FUNDING: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome.

Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist-based trials.

Lupus miliaris disseminatus faciei in a young male.

We report a case of a healthy 26-year-old male with multiple asymptomatic reddish papules and papule-nodules on the central area of the face, persisting from more than 2 months and gradually increasing in number. An incisional skin biopsy revealed a confluent dense granulomatous infiltrate centred by large areas of eosinophilic necrosis consistent with the diagnosis of lupus miliaris disseminatus faciei (LMDF). This is a rare dermatosis first described in 1878 by Fox, that often poses a clinical challenge as it is a disease process which is difficult to diagnose. In fact, in our case, a diagnosis of LMDF was made on skin biopsy. We think that collaboration among dermatologists and General Practitioners is very important for diagnosis of rare dermatosis and especially for management of it, in order to prevent the development of depressed scars.

Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: A hospital-based case-control study.

Polychlorinated biphenyls (PCB) have been classified by the International Agency for Research on Cancer (IARC) in Group 1 as carcinogenic to human, based on sufficient evidence in humans of an increased risk of cutaneous malignant melanoma (CMM), however few studies have been done in the general population. This study examined the relationship between PCB plasma levels and risk of CMM adjusting for sun sensitivity and sun exposure in a province of Northern Italy (Brescia), where a chemical factory produced PCBs from 1938 to 1984 causing human contamination. A case-control study of 205 CMM patients and 205 control subjects was conducted. Cases and controls were assayed for plasma levels of 33 PCB congeners. No associations was found between risk of CMM and plasma levels of total PCB (OR = 0.81; 95% CI: 0.34-1.96 for highest vs lowest quartile) or specific congeners. The study confirmed the association with light skin colour (OR = 3.00; 95% CI: 1.91-4.73), cumulative lifetime UV exposure (OR = 2.56; 95% CI: 1.35-4.85) and high level of education (OR = 1.45; 95% CI: 1.03-2.05). This case-control study does not support the hypothesis of an association between current plasma levels of PCBs and CMM development in the general population.

Melanoma in the elderly.

BACKGROUND: Among older patients, melanoma in general presents biological features related to a more aggressive biology, such as more locally advanced tumor. Management of melanoma in elderly may be difficult, mainly due to comorbidities. We report the experience of the Melanoma Unit of ASST Spedali Civili in Brescia, Italy. METHODS: Study subjects were drawn from 3444 patients with histological confirmed melanoma. Data were extracted from electronic database of the Melanoma Unit of ASST Spedali Civili in Brescia, Italy. Patients who received diagnosis of cutaneous melanoma at age of 65 years or older were retrospectively evaluated. For each diagnosed melanoma, histological characteristics, treatment, and outcomes were evaluated. RESULTS: Of the 805 patients described in this study, 444 were males and 361 females. Statistically significant differences were found between patients aged 65-80 years and those aged >80 years considering melanoma prognostic factors, such as Breslow thickness, number of mitoses/mm2 and ulceration. CONCLUSIONS: Older age is recognized as an independent poor prognostic factor in melanoma patients, and melanoma in older patients have a distinct natural history. It was found that management of cancer in old person represents a major challenge to medical practice. We believe that the choice of therapy should be individualized and based upon the individual's overall health and that, particularly in these cases, management often requires interdisciplinary cooperation between dermatologist, surgical specialist, oncologist and geriatrician.

Genetic counselling and high-penetrance susceptibility gene analysis reveal the novel CDKN2A p.D84V (c.251A>T) mutation in melanoma-prone families from Italy.

Genetic susceptibility to primary cutaneous melanoma (PCM) may account for up to 12% of PCMs, presenting as the familial atypical mole/multiple melanoma syndrome (FAMMM), an autosomal dominant condition with incomplete penetrance and variable expressivity, characterized by PCM in at least two relatives and/or more than one PCMs in the same patient. To identify individuals at high genetic risk of PCM, from 1 January 2012 to 31 December 2015, we offered genetic counselling and molecular analysis of the two high-penetrance FAMMM susceptibility genes, cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4), to 92 consecutive, unrelated patients with FAMMM. Age at diagnosis and number of PCMs were obtained from medical records; the number of PCMs and affected relatives were recorded for each family. The diagnostic work-up consisted of genetic counselling and cascade genetic testing in patients and further extension to relatives of those identified as mutation carriers. All exons and exon/intron boundaries of CDKN2A and CDK4 genes were screened by direct bidirectional sequencing. We identified CDKN2A mutations in 19 of the 92 unrelated patients (20.6%) and in 14 additional, clinically healthy relatives. Eleven of these latter subsequently underwent excision of dysplastic nevi, but none developed PCM during a median follow-up of 37.3 months. In three patients from unrelated families, the novel CDKN2A p.D84V (c.251A>T) mutation was observed, associated with PCM in each pedigree. Genetic screening of FAMMM patients and their relatives can contribute towards specific primary and secondary prevention programmes for individuals at high genetic risk of PCM. The novel CDKN2A p.D84V (c.251A>T) mutation adds to the known mutations associated with FAMMM.

Melanoma density and relationship with the distribution of melanocytic naevi in an Italian population: a GIPMe study--the Italian multidisciplinary group on melanoma.

The most frequent site for melanoma is the back in men and the lower limbs in women, where intermittent sun exposure has been reported to be an environmental agent, although studies on age-specific incidence have suggested that melanoma in chronically sun-exposed areas, such as the face, increases with age. To identify the preferential development of melanoma in chronically or intermittently sun-exposed areas and the relationship between body site distribution and parameters such as sex, age, distribution of melanocytic naevi, atypical naevi and actinic keratoses, a prospective epidemiological multicentre study was carried out on all the consecutive melanoma cases diagnosed in a 2-year period from 27 Italian GIPMe centres (GIPMe: the Italian Multidisciplinary Group on Melanoma). Both the relative density of melanoma (RDM), defined as the ratio between observed and expected melanoma for a specific body site, and the average nevi density were identified. The most common melanoma site was the back, a factor that was not affected by either age or sex, even if men had higher density values. Statistically significant higher RDM values were observed in women aged more than 50 years for leg lesions and in the anterior thighs for young women (<50 years), whereas the lowest values were observed in the posterior thighs in women of any age. Facial RDM was statistically significantly higher than expected in both male and female patients more than 50 years of age. Melanoma was associated with a significantly higher atypical naevi density only for the back, chest and thighs. Indeed, facial melanoma was related to the presence of more than four actinic keratoses and not naevi density. To the best of our knowledge, the RDM method was applied for the first time together with naevus density calculation to obtain these data, which strongly substantiate the 'divergent pathway' hypothesis for the development of melanoma, but not find a direct correlation between melanoma and nevi for each anatomical site.