28th Italian Melanoma Intergroup National Congress

The proceedings contain 35 papers. The topics discussed include: germline variants and prognostic factors for cutaneous melanoma in children and adolescents;association between polygenic risk score and multiple primary melanoma;Porocarcinoma: an epidemiological, clinical, and dermoscopic 20-year study;primary cutaneous melanoma and COVID-19: a hospital-based study;atypical spitz tumors: an epidemiological, clinical and dermoscopic multicenter study with 16 years of follow-up;pediatric melanoma: an epidemiological, clinical and dermoscopic multicenter study;recurrence-free survival prediction in melanoma patients by exploiting artificial intelligence techniques on melanoma whole slide images;ultra-high frequency ultrasound and machine learning approaches for the differential diagnosis of melanocytic lesions;and genetic determinants of response to therapy in a real-world setting of advanced/metastatic melanoma patients: whole-exome sequencing and CFDNA analysis.

Effect of polycyclic aromatic hydrocarbons on skin pigmentation

Despite COVID-19 lockdowns, gradual restarting of the global economy has rapidly increased air quality index (AQI) values. With over 99 % of the world population living in areas exceeding air quality guidelines, air pollution is more so a threat to our health. Within particulate matter, a major air pollutant, lies polycyclic aromatic hydrocarbons (PAH). While recent studies explore the link between air pollution and pigmentation disorders, the molecular mechanisms responsible for this alteration remain largely unknown. To challenge our hypothesis that exposure to PAH leads to an increase in abnormal pigmentation, we have utilized in vitro and in vivo assays. In vitro, novel 2D and 3D co-culture assays were developed to analyze pigment production, transfer and total melanin content in human keratinocytes and melanocytes. Following that, bulk RNA-sequencing was also carried out on isolated melanocytes post co-culture to possibly elucidate the mechanism behind this phenomenon. In vivo, a mouse model bearing epidermal melanin was generated to investigate the effect of PAH exposure. Notably, our initial studies have indicated a significant increase in melanin production, transfer and total melanin content when exposed to PAH. From our transcriptome analysis, we have also pinpointed to several genes which have been differentially expressed, most significant being CYP1A1. This prompted us to look further into the AhR signaling pathway. Interestingly, we did not see an increase in classic melanogenesis genes, but instead genes which are usually associated with senescence-associated secretory phenotype (SASP). This hints to a possible alternative pathway leading to an eventual increase in melanin production. We believe that our findings highlight potential approaches for novel therapeutics the treatment of skin pigmentation disorders triggered by air pollution.Copyright © 2023

NEUROCUTANEOUS MELANOCYTOSIS WITH MANIFESTATION IN ADULTHOOD.

A 20-year-old patient was presented with subacute onset of headache, nausea and vomiting. Testing of nasal/oropharyngeal swabs indicated the presence of SARS-CoV-2 RNA, and later the antibodies to this virus were found. The treatment in the hospital for Coronavirus 19 Disease (COVID-19) provided only temporary relief, and the patient then was referred to the Regional Stroke Center (RSC) to exclude a subarachnoid hemorrhage. RSC neurologists drew attention to multiple skin nevi in the patient. Brain MRI demonstrated abnormal T1 hyperintensity in the brain leptomeninges, with leptomeningeal contrast enhancement as well as hyperintensity in amygdala regions on T1 weighted images, bilaterally. The anomaly of the Dandy-Walker malformation complex was also revealed. Cerebrospinal fluid (CSF) analysis showed elevated protein (0.52 g/L), low lymphocytosis (lymphocytes, 6 in mm3), and decreased glucose (1.8 mmol/L). Neurocutaneous melanocytosis (NCM) was diagnosed, which neurological manifestation was probably triggered by COVID-19. The patient's vision gradually progressively worsened. In 2.5 months after the clinical manifestation of NCM, fundoscopy revealed optic discs atrophy (despite the absence of previous edema), and repeated CSF analysis showed atypical cells with characteristics corresponding to melanoma. Malignant transformation of cerebral melanocytosis was suspected, and the patient was referred to an oncological dispensary for further therapy. In the presented literature review, special attention is paid to the issues of neuroimaging, cytological and immunocytochemical diagnostics of NCM.Copyright © Russian Neurological Journal. All rights reserved.

NEUROCUTANEOUS MELANOCYTOSIS WITH MANIFESTATION IN ADULTHOOD.

A 20-year-old patient was presented with subacute onset of headache, nausea and vomiting. Testing of nasal/oropharyngeal swabs indicated the presence of SARS-CoV-2 RNA, and later the antibodies to this virus were found. The treatment in the hospital for Coronavirus 19 Disease (COVID-19) provided only temporary relief, and the patient then was referred to the Regional Stroke Center (RSC) to exclude a subarachnoid hemorrhage. RSC neurologists drew attention to multiple skin nevi in the patient. Brain MRI demonstrated abnormal T1 hyperintensity in the brain leptomeninges, with leptomeningeal contrast enhancement as well as hyperintensity in amygdala regions on T1 weighted images, bilaterally. The anomaly of the Dandy-Walker malformation complex was also revealed. Cerebrospinal fluid (CSF) analysis showed elevated protein (0.52 g/L), low lymphocytosis (lymphocytes, 6 in mm3), and decreased glucose (1.8 mmol/L). Neurocutaneous melanocytosis (NCM) was diagnosed, which neurological manifestation was probably triggered by COVID-19. The patient's vision gradually progressively worsened. In 2.5 months after the clinical manifestation of NCM, fundoscopy revealed optic discs atrophy (despite the absence of previous edema), and repeated CSF analysis showed atypical cells with characteristics corresponding to melanoma. Malignant transformation of cerebral melanocytosis was suspected, and the patient was referred to an oncological dispensary for further therapy. In the presented literature review, special attention is paid to the issues of neuroimaging, cytological and immunocytochemical diagnostics of NCM.Copyright © Russian Neurological Journal. All rights reserved.

Melanoma of unknown primary: a case series and review of the literature

Melanoma of unknown primary (MUP) was originally defined in 1963 as melanoma in the subcutaneous tissue, lymph nodes or visceral organs without the presence of a cutaneous, ocular or mucosal primary. The incidence of MUP is reported to be between 1% and 8% of all melanomas. MUP can be divided into lymph node involvement only and organ metastases. The aetiology of MUP is elusive. Possibilities proffered include an unrecognized melanoma, a previously excised melanoma that was misdiagnosed as benign, a primary melanoma that has completely regressed or the de novo malignant transformation of an aberrant melanocyte within a lymph node. We report our experience in a single tertiary referral centre. A database of all melanomas diagnosed between January 2018 and December 2021 was analysed for MUP. The total number of melanomas diagnosed in that timeframe was 298. Six patients (three males, three females) were identified as having MUP, with an incidence of 2%. Median age was 63.3 years (range 45-84). One (17%) presented with primary dermal metastatic deposits, 67% (n = 4) presented with isolated lymph node metastases, 0% presented with visceral metastases and 17% (n = 1) presented with isolated brain metastases. All six patients were reviewed by dermatology and ophthalmology. Fifty per cent (n = 3) were reviewed by ENT. One (17%) was referred to gynaecology. No primary melanoma was identified in any of the patients. All patients underwent a positron emission tomography-computed tomography (CT) scan to investigate for further metastases, and all underwent dedicated brain imaging via CT and magnetic resonance imaging. All patients underwent surgical resection of their MUP, and all were reviewed by medical oncology, with 83% (n = 5) undergoing treatment with immunotherapy. There have been no associated deaths to date. In five patients (83%) the MUP was diagnosed in 2021, and one (17%) was diagnosed in 2018. Recent studies have shown the impact of the COVID- 19 pandemic on the presentation of cutaneous melanoma, including an increased Breslow thickness at the time of presentation vs. a similar period pre-COVID-19. Our data indicate an increased rate of MUP presenting after the onset of the COVID-19 pandemic;however, given the low number overall, no conclusions can be drawn. There is no current literature regarding the increased rate of MUP since the COVID-19 pandemic. Further studies are required to investigate this. Recommendations for the evaluation of those with MUP include a full skin examination by a dermatologist and ocular examination to exclude primary melanoma. Patients should undergo imaging of the brain, thorax, abdomen and pelvis to assess disease burden. Referral to otorhinolaryngology can be considered to assess for mucosal melanoma of the nasopharynx. Gynaecology referral should be considered for those with inguinal lymphadenopathy. MUP is rare. Guidelines for the investigation of MUP are currently lacking and are needed to ensure the delivery of consistent evidence-based care for patients.

Multidisciplinary management of a quickly growing pediatric atypical Spitz nevus, mimicking melanoma, during the COVID-19 pandemic

Spitzoid melanoma is very rare tumour in the pediatric population, with clinical and non-uniform behaviour, different from adult melanoma [1]. It can be difficult to differentiate an atypical Spitz nevus from a Spitzoid melanoma, resulting in diagnostic problems. In addition, in our clinical case, the COVID-19pandemiccaused significant delays both in the diagnosis and in the surgical treatment of our patient. We present the clinical case of a 4-year-old child suffering from a localized polypoid cutaneous neoformation on the dorsum of the left hand, which started immediately before the lockdown and steadily increased during the COVID-19 pandemic. After a general clinical framing, the child underwent an excisional biopsy at our Department of Plastic and Reconstructive Surgery, at the Policlinico of Foggia. Subsequently, two independent anatomic pathology groups examined the specimen. Definitive diagnosis was made only after careful genetic analysis in combination with supporting histological and immunohistochemical examinations. This clinical case shows how during the pandemic we have been facing advanced forms of tumours, compared to the previous period and highlight show an interdisciplinary and multicenter collaboration allowed a quick diagnosis of certainty, demonstrating the utility of molecular pathology as a fundamental aid in clinical/surgical practice. © 2022 The Authors

Activation of Melanocortin Receptors as a Potential Strategy to Reduce Local and Systemic Reactions Induced by Respiratory Viruses.

The clinical hallmarks of infections caused by critical respiratory viruses consist of pneumonia, which can progress to acute lung injury (ALI), and systemic manifestations including hypercoagulopathy, vascular dysfunction, and endotheliitis. The disease outcome largely depends on the immune response produced by the host. The bio-molecular mechanisms underlying certain dire consequences of the infection partly arise from an aberrant production of inflammatory molecules, an event denoted as "cytokine storm". Therefore, in addition to antiviral therapies, molecules able to prevent the injury caused by cytokine excess are under investigation. In this perspective, taking advantage of melanocortin peptides and their receptors, components of an endogenous modulatory system that exerts marked anti-inflammatory and immunomodulatory influences, could be an effective therapeutic strategy to control disease evolution. Exploiting the melanocortin system using natural or synthetic ligands can form a realistic basis to counteract certain deleterious effects of respiratory virus infections. The central and peripheral protective actions exerted following melanocortin receptor activation could allow dampening the harmful events that trigger the cytokine storm and endothelial dysfunction while sustaining the beneficial signals required to elicit repair mechanisms. The long standing evidence for melanocortin safety encourages this approach.