Acral lentiginous melanoma histotype predicts outcome in clinical stage I-II melanoma patients: an International multicenter study.

BACKGROUND: In the American Joint Committee on Cancer (AJCC) classification, acral lentiginous melanoma (ALM) histotype ALM is not included as an independent prognostic factor; in small series its negative prognostic impact on disease-free survival (DFS) and overall survival (OS) has been linked to the greater Breslow thickness (BT). PATIENTS AND METHODS: The study was carried out at four referral melanoma centers (three Italian and one Polish). Clinical consecutive patients with stage I-II melanoma, who were diagnosed, treated, and followed up between January 1998 and March 2018 in annotated specific databases were included. RESULTS: Overall, 6734 were evaluable, 4349 with superficial spreading melanoma (SSM), 2132 with nodular melanoma (NM), and 253 with ALM. At univariable analysis, a statistically significant worse DFS [hazard ratio (HR) 2.72, 95% confidence interval (CI) 2.24-3.30; P < 0.001] and OS (HR 2.67, 95% CI 2.15-3.32; P < 0.001) were found in patients with ALM compared with SSM. Similarly, the NM histotype was associated with a worse prognosis compared with the SSM histotype (DFS: HR 2.29, 95% CI 2.08-2.52; P < 0.001 and OS: HR 2.21, 95% CI 1.99-2.46; P < 0.001). At multivariable analysis, after adjusting for age, sex, BT, ulceration, and the sentinel lymph node status, a statistically significant worse DFS [adjusted HR (aHR; ALM versus SSM) 1.25, 95% CI 1.02-1.52; P = 0.028] was confirmed for patients with ALM. For patients with NM, instead, no impact of histology was found in terms of DFS [aHR (NM versus SSM) 1.04, 95% CI 0.93-1.15; P = 0.513] and OS [aHR (NM versus SSM) 0.96, 95% CI 0.86-1.08; P = 0.548]. CONCLUSIONS: ALM is associated with a worse long-term DFS. Our results could have important clinical implications for patients' stratification in future clinical trials and the incorporation of ALM histotype in the new AJCC classification as an independent prognostic factor.

Melanoma in children and adolescents: analysis of susceptibility genes in 123 Italian patients.

BACKGROUND: A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients. OBJECTIVE: We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents. METHODS: One-hundred-twenty-three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico-pathological characteristics was evaluated. RESULTS: Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi. CONCLUSION: Our results confirm the scarce involvement of the major high-risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.

Habitat suitability mapping of the black coral Leiopathes glaberrima to support conservation of vulnerable marine ecosystems.

The black coral Leiopathes glaberrima is an important habitat forming species that supports benthic biodiversity. Due to its high sensitivity to fishing activities, it has been classified as indicator of Vulnerable Marine Ecosystems (VMEs). However, the information on its habitat selection and large-scale spatial distribution in the Mediterranean Sea is poor. In this study a thorough literature review on the occurrence of L. glaberrima across the Mediterranean Sea was undertaken. Predictive modelling was carried out to produce the first continuous map of L. glaberrima suitable habitat in the central sector of the Mediterranean Sea. MaxEnt modeling was used to predict L. glaberrima probability of presence as a function of seven environmental predictors (bathymetry, slope, aspect North-South and East-West, kinetic energy due to currents at the seabed, seabed habitat types and sea bottom temperature). Our results show that bathymetry, slope and aspect are the most important factors driving L. glaberrima spatial distribution, while in less extent the other environmental variables. This study adds relevant information on the spatial distribution of vulnerable deep water corals in relation to the environmental factors in the Mediterranean Sea. It provides an important background for marine spatial planning especially for prioritizing areas for the conservation of VMEs.

Scrotal cutaneous metastasis from rectal squamous cell carcinoma: a rare evolution into a rare tumor.

The scrotum is a rare site for metastases and represents less than 1% of the body's total surface area. Clinically, metastatic deposits in the scrotum can present in a variety of ways. They may appear as solitary cutaneous nodules, papules, plaques, or generalized induration or edema. Indeed, scrotum metastasis may be mistaken for other skin lesions since several dermatologic conditions can present with inflammation or dermatitis of the scrotum. Properly diagnosing cutaneous metastasis requires histopathological examination since the clinical appearances are, as described, highly variable and non-specific. We present a 63-year-old man with painless nodules on the scrotal skin. Excisional biopsy of the nodules revealed a metastasis from rectal squamous cell carcinoma. The incidence of this kind of tumors is estimated around 0.1-0.25 per 1000 colorectal neoplasms.

The prognostic impact of the extent of ulceration in patients with clinical stage I-II melanoma: a multicentre study of the Italian Melanoma Intergroup (IMI).

BACKGROUND: The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM). OBJECTIVES: To investigate whether the extent of ulceration (EoU) predicts relapse-free survival (RFS) and overall survival (OS) in PCM. MATERIALS AND METHODS: We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU. RESULTS: A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS [hazard ratio (HR) (1-mm increase) 1·26, 95% confidence interval (CI) 1·08-1·48, P = 0·0047] and OS [HR (1-mm increase) 1·25, 95% CI 1·05-1·48, P = 0·0120] was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour-infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01-4 mm and > 4 mm BT. CONCLUSIONS: This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports.

What is in our seas? Assessing anthropogenic litter on the seafloor of the central Mediterranean Sea.

Abundance, composition, and distribution of macro-litter found on the seafloor of the Strait of Sicily between 10 and 800 m depth has been studied using data collected by bottom trawl surveys MEDITS from 2015 to 2019. Three waste categories based on the items use were considered: single-use, fishing-related and generic-use. Over 600 sampling sites, just 14% of these were litter-free. The five-years average density of seafloor litter was 79.6 items/km2 and ranged between 46.8 in 2019 and 118.1 items/km2 in 2015. The predominant waste type was plastic (58% of all items). Regardless of material type, single-use items were a dominant (60% of items) and widespread (79% of hauls) fraction of litter with a mean density of 48.4 items/km2. Fishing-related items accounted for 12% of total litter items. Percentage of dirty hauls and litter density increased with depth. Analysis of the relation density-depth indicates a progressive increase of litter density beyond depth values situated within the interval 234-477 m depending on the litter category. A significant decrease in litter density by categories was observed over the period. Patterns of spatial distribution at the higher depths (200-80 0m) resulted stable over the years. Density hotspots of fishing-related items were found where the fishing activity that uses fish aggregating devices (FADs) is practised and in the proximity of rocky banks. Single-use and generic-use objects densities were greater on the seafloor along main maritime routes than other areas. Comparisons between the percentage of hauls littered with anthropic waste from the mid-1990s against those in 2018-19 highlighted an increase of about 10.8% and 15.3% for single-use items and fishing-related items respectively, and a decrease of 18.6% for generic-use items. This study provides a snapshot of the current situation of littering in the central Mediterranean Sea and represents a solid baseline against which the effectiveness of current and future mitigation strategies of the litter impact on marine environment can be measured.

Cutaneous leiomyosarcoma: a clinical, dermoscopic, pathologic case study.

Cutaneous leiomyosarcoma is a rare malignant mesenchymal tumor of smooth muscle origin of unknown etiology. Leiomyosarcomas located on the skin include superficial leiomyosarcomas and metastatic leiomyosarcomas. Superficial leiomyosarcomas represent 7-10% of all cases of leiomyosarcoma and are subdivided into cutaneous and subcutaneous lesions based on skin location. We report a case of an 81-year-old woman who presented a slow growing tender single nodule on the left thigh and describe its clinical and dermoscopic features.

The burden of cutaneous adnexal carcinomas and the risk of associated squamous cell carcinoma: a population-based study.

BACKGROUND: Recent studies have shown an increasing incidence of cutaneous adnexal carcinomas (CACs). OBJECTIVES: The aim of our study was to evaluate incidence and survival for cases of CACs and investigate their association with other skin neoplasms. METHODS: We conducted a population-based study. Data on incident cases of CACs were obtained from the Tuscany Cancer Registry between 1985 and 2010. In order to determine whether the occurrence of squamous cell carcinoma (SCC) among patients with CAC is higher or lower than expected in the general population, the standardized incidence ratio (SIR) was calculated. RESULTS: A total of 242 patients with CAC were observed; the age-standardized incidence rate was 3·8 cases per million person-years. From 1997 to 2010 crude incidence rates increased by 159%. Age-specific incidence was higher in men over 80 years old than in women of the same age and younger individuals. Carcinomas of sweat gland origin prevailed; the most common histotype was porocarcinoma and the most frequently affected site was the head/neck. Overall, 88% of CACs were diagnosed at a localized stage. The 5-year overall survival and disease-specific survival rates were 59% [95% confidence interval (CI) 53-65] and 94% (95% CI 91-98), respectively. In the observation cohort, the number of SCCs was significantly higher than expected as the SIR was calculated to be 33·7 (P < 0·001). CONCLUSIONS: Increasing incidence warrants awareness and early diagnosis of CACs. Increased SCC incidence among patients with these tumours highlights the relevance of careful skin examination and follow-up.

Species distribution models of two critically endangered deep-sea octocorals reveal fishing impacts on vulnerable marine ecosystems in central Mediterranean Sea.

Deep-sea coral assemblages are key components of marine ecosystems that generate habitats for fish and invertebrate communities and act as marine biodiversity hot spots. Because of their life history traits, deep-sea corals are highly vulnerable to human impacts such as fishing. They are an indicator of vulnerable marine ecosystems (VMEs), therefore their conservation is essential to preserve marine biodiversity. In the Mediterranean Sea deep-sea coral habitats are associated with commercially important crustaceans, consequently their abundance has dramatically declined due to the effects of trawling. Marine spatial planning is required to ensure that the conservation of these habitats is achieved. Species distribution models were used to investigate the distribution of two critically endangered octocorals (Funiculina quadrangularis and Isidella elongata) in the central Mediterranean as a function of environmental and fisheries variables. Results show that both species exhibit species-specific habitat preferences and spatial patterns in response to environmental variables, but the impact of trawling on their distribution differed. In particular F. quadrangularis can overlap with fishing activities, whereas I. elongata occurs exclusively where fishing is low or absent. This study represents the first attempt to identify key areas for the protection of soft and compact mud VMEs in the central Mediterranean Sea.

The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600.

BACKGROUND: BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP. METHODS: PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAF(V600)-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining. RESULTS: Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P < 0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P < 0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P < 0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P < 0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P < 0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P < 0.002) were independent prognostic factors for melanoma-specific survival. CONCLUSION: Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAF(V600)-mutated MMP treated with BRAFi.

Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease.

BACKGROUND: Histopathological diagnosis including selection of lesions, the determination of the best point of time for biopsy and workup is not trivial in cutaneous graft-versus-host disease (GvHD). OBJECTIVES: To develop interdisciplinary recommendations on performing, the laboratory work up and reporting of the results of skin biopsies in patients with suspected cutaneous GvHD. METHODS: A working group consisting of dermatopathologists, dermatologists, transplant-physicians and transplant-pathologists prepared recommendations for performing skin biopsies, laboratory workup and evaluation of tissue samples, and reporting of the results in patients with cutaneous GvHD. After achieving a consensus within the working group, a survey that comprised the core issues of the recommendations was electronically sent out to 72 alloHSCT centres within Germany, Austria, and Switzerland and their Departments of Pathology. The answers were discussed in a Consensus Conference and final recommendations were established. RESULTS: Twenty-five centres responded to the clinical and 17 centres to the histopathological survey. Questions addressed to the clinicians comprised the indication for skin biopsy in chronic GvHD (cGvHD) and acute GvHD (aGvHD) and the appropriate point of time for skin biopsy. Eighty-eight per cent agreed that the skin biopsy is generally indicated in patients with suspected cGvHD lacking diagnostic features. In contrast, with suspected aGvHD, only 62% of respondents felt that skin biopsy was necessary even if GvHD had not been confirmed in another organ. Although restricted due to the fact that immunosuppression is often applied in an emergency setting most centres supported skin biopsies before initiation of topical or systemic immunosuppression. The majority of pathologists agreed that in non-sclerotic GvHD a punch biopsy is adequate, whereas in sclerotic GvHD a scalpel biopsy is preferred. CONCLUSION: While a consensus on the need for biopsies in cGvHD was reached the value of skin biopsies in aGvHD and subsequent biopsies during therapy requires further evaluation.

CDKN2A mutations could influence the dermoscopic pattern of presentation of multiple primary melanoma: a clinical dermoscopic genetic study.

BACKGROUND: Patients who develop cutaneous melanoma are at increased risk of developing a second primary melanoma. There are many aetiological reasons by which the risk of a second melanoma increases. Among others, genetic factors may contribute to modulating this risk. The risk of identifying a CDKN2A germline mutation increases with the number of primary melanomas and with the presence of familial history of melanoma. Patients with melanoma are especially encouraged to have regular follow-up visits with their dermatologist to perform clinical and dermatoscopic examination. In particular, dermoscopy could be very useful in multiple primary melanoma (MPM) patients. OBJECTIVES: To analyse the clinical and dermatoscopic features of multiple melanomas, focusing on those features that are more frequently found in the same patient to recognize them earlier and understand whether they appear with the similar peculiar dermatoscopic features, especially in CDKN2A carriers. METHODS: Medical records of MPM patients were selected from a database including 1065 patients with histopathologically proven melanoma diagnosis, all treated at the dermatology clinic of the University of Florence from 2000 to 2013. Pictures of melanoma were independently and blindly administered to three dermatologist experts in dermoscopy to evaluate the presence or absence of ABCD criteria for each clinical image, and the main pattern for the dermoscopic images. The results were then analyzed and crossed to rate the clinical and dermoscopic features of MPM. RESULTS: Seventy five (7.0%) of 1065 patients included in our database were found to carry an MPM disease. Among them, we selected 12 (16%) patients with three or more MPMs. The presence of the CDKN2A melanoma susceptibility gene was observed in 4/12 (33.33%) patients; two patients presented the C500G and c.5 + 1delG polymorphisms in the CDKN2A gene. In CDKN2A carriers, each patient showed a similar and specific dermatoscopic pattern in their lesions. CONCLUSIONS: Even being aware of the limitations of this study, according to hereditary characters and their modes of transmissions, we could speculate that for each patient with a CDKN2A germline mutation, it is possible to find the same kind of dermoscopical pattern among their melanocytic tumours.

Acral lentiginous melanoma treated with topical imiquimod cream: possible cooperation between drug and tumour cells.

An 85-year-old woman presented with a lesion on the sole of her right foot, which was histologically confirmed as acral lentiginous melanoma. Because of the large field involved and because the patient refused any invasive or painful treatment, topical treatment with imiquimod was commenced. At the 20-month follow-up, the patient was still continuing treatment with topical imiquimod, and no metastases to the lymph nodes or viscera were found, either clinically or in imaging studies. We believe that the success of the treatment cannot be explained only by the stimulation of the immune system induced by imiquimod. A possible explanation might be 'tumour dormancy', where a tumour grows very slowly because of a balance between the neoplasia and the immune (and nonimmune) mechanisms of tumour control. The use of imiquimod has so far allowed our patient to avoid surgery, and perturbation of the mechanisms of tumour regulation, such as local immunity and angiogenesis, has not taken place.