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.

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.

Pigmented nodular melanoma: the predictive value of dermoscopic features using multivariate analysis.

BACKGROUND: Nodular melanoma (NM), representing 10-30% of all melanomas, plays a major role in global mortality related to melanoma. Nonetheless, the literature on dermoscopy of NM is scanty. OBJECTIVES: To assess odds ratios (ORs) to quantify dermoscopic features of pigmented NM vs. pigmented superficial spreading melanoma (SSM), and pigmented nodular nonmelanocytic and benign melanocytic lesions. METHODS: To assess the presence or absence of global patterns and dermoscopic criteria, digitized images of 457 pigmented skin lesions from patients with a histopathological diagnosis of NM (n = 75), SSM (n = 93), and nodular nonmelanocytic and benign melanocytic lesions (n = 289; namely, 39 basal cell carcinomas, 85 seborrhoeic keratoses, 81 blue naevi, and 84 compound/dermal naevi) were retrospectively collected and blindly evaluated by three observers. RESULTS: Multivariate analysis showed that ulceration (OR 4.07), homogeneous disorganized pattern (OR 10.76), and homogeneous blue pigmented structureless areas (OR 2.37) were significantly independent prognostic factors for NM vs. SSM. Multivariate analysis of dermoscopic features of NM vs. nonmelanocytic and benign melanocytic lesions showed that the positive correlating features leading to a significantly increased risk of NM were asymmetric pigmentation (OR 6.70), blue-black pigmented areas (OR 7.15), homogeneous disorganized pattern (OR 9.62), a combination of polymorphous vessels and milky-red globules/areas (OR 23.65), and polymorphous vessels combined with homogeneous red areas (OR 33.88). CONCLUSIONS: Dermoscopy may be helpful in improving the recognition of pigmented NM by revealing asymmetric pigmentation, blue-black pigmented areas, homogeneous disorganized pattern and abnormal vascular structures, including polymorphous vessels, milky-red globules/areas and homogeneous red areas.

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.

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.

Direct T cell-tumour interaction triggers TH1 phenotype activation through the modification of the mesenchymal stromal cells transcriptional programme.

BACKGROUND: Mesenchymal stromal cells (MSCs) are heterogeneous cells with immunoregulatory and wound-healing properties. In cancer, they are known to be an essential part of the tumour microenvironment. However, their role in tumour growth and rejection remains unclear. To investigate this, we co-cultured human MSCs, tumour infiltrating lymphocytes (TIL), and melanoma cells to investigate the role of MSCs in the tumour environment. METHODS: Mesenchymal stromal cells were co-cultured with melanoma antigen-specific TIL that were stimulated either with HLA-A*0201(+) melanoma cells or with a corresponding clone that had lost HLA-A*0201 expression. RESULTS: Activated TIL induced profound pro-inflammatory gene expression signature in MSCs. Analysis of culture supernatant found that MSCs secreted pro-inflammatory cytokines, including TH1 cytokines that have been previously associated with immune-mediated antitumor responses. In addition, immunohistochemical analysis on selected markers revealed that the same activated MSCs secreted both the TH1 cytokine (interleukin-12) and indoleamine 2,3 dioxygenase (IDO), a classical immunosuppressive factor. CONCLUSIONS: This study reflected that the plasticity of MSCs is highly dependent upon microenvironment conditions. Tumour-activated TIL induced TH1 phenotype change in MSCs that is qualitatively similar to the previously described immunologic constant of rejection signature observed during immune-mediated, tissue-specific destruction. This response may be responsible for the in loco amplification of antigen-specific anti-cancer immune response.

Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

Cutaneous squamous cell carcinoma (CSCC) accounts for ∼20%-25% of all skin tumors. Its precise incidence is often challenging to determine due to limited statistics and its incorporation with mucosal forms. While most cases have a favorable prognosis, challenges arise in patients presenting with locally advanced or metastatic forms, mainly appearing in immunocompromised patients, solid organ transplantation recipients, or those facing social difficulties. Traditionally, chemotherapy and targeted therapy were the mainstays for advanced cases, but recent approvals of immunotherapeutic agents like cemiplimab and pembrolizumab have revolutionized treatment options. These guidelines, developed by the Italian Association of Medical Oncologists (AIOM) using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, aim to guide clinicians in diagnosing, treating, and monitoring patients with CSCC, covering key aspects from primitive tumors to advanced stages, selected by a panel of experts selected by AIOM and other national scientific societies. The incorporation of these guidelines into clinical practice is expected to enhance patient care and address the evolving landscape of CSCC management.

IRF-1 responsiveness to IFN-γ predicts different cancer immune phenotypes.

BACKGROUND: Several lines of evidence suggest a dichotomy between immune active and quiescent cancers, with the former associated with a good prognostic phenotype and better responsiveness to immunotherapy. Central to such dichotomy is the master regulator of the acute inflammatory process interferon regulatory factor (IRF)-1. However, it remains unknown whether the responsiveness of IRF-1 to cytokines is able to differentiate cancer immune phenotypes. METHODS: IRF-1 activation was measured in 15 melanoma cell lines at basal level and after treatment with IFN-γ, TNF-α and a combination of both. Microarray analysis was used to compare transcriptional patterns between cell lines characterised by high or low IRF-1 activation. RESULTS: We observed a strong positive correlation between IRF-1 activation at basal level and after IFN-γ and TNF-α treatment. Microarray demonstrated that three cell lines with low and three with high IRF-1 inducible translocation scores differed in the expression of 597 transcripts. Functional interpretation analysis showed mTOR and Wnt/ß-cathenin as the top downregulated pathways in the cell lines with low inducible IRF-1 activation, suggesting that a low IRF-1 inducibility recapitulates a cancer phenotype already described in literature characterised by poor prognosis. CONCLUSION: Our findings support the central role of IRF-1 in influencing different tumour phenotypes.

CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2.

BACKGROUND: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. METHODS: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). RESULTS: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. CONCLUSION: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.

Oestrogen receptor beta and melanoma: a comparative study.

BACKGROUND: Oncological research has focused on evaluating oestrogen receptors (ERs) in oestrogen-related tumours, and understanding the potential role of ERs in the pathophysiology of cancer. OBJECTIVES: To investigate the significance of oestrogen receptor beta (ERß) in melanoma. METHODS: We prospectively evaluated ERß expression in malignant melanoma (MM) tissue and adjacent healthy skin by quantitative immunohistochemistry at the Department of Dermatology of the University of Florence, from 1998 to 2010. RESULTS: ERß was detected with varying staining intensity in the 66 malignant melanocytic lesions. After adjusting for age and sex, we found that ERß expression was significantly lower in melanoma tissue compared with adjacent healthy skin (P < 0·0001). We also found significantly lower ERß levels in thick melanoma tissue compared with thin melanoma tissue. In addition, there was a positive association between Breslow thickness and the difference of ERß expression between healthy tissue and melanoma tissue (P = 0·0004). Consistent with sex differences in melanoma survival, men showed significantly lower levels of ERß than women in both melanoma (P = 0·05) and healthy tissues (P = 0·02). CONCLUSIONS: ERß expression is inversely associated with Breslow thickness and is significantly influenced by sex in MM.

Dermoscopy of acral melanoma: a multicenter study on behalf of the international dermoscopy society.

BACKGROUND: Most studies on dermoscopy of acral lesions were conducted in Asian populations. In this study, we analyzed these features in a predominantly Caucasian population. OBJECTIVE: Estimate the prevalence of dermoscopic features in acral lesions, and assess their level of agreement between observers. METHODS: In this retrospective multicenter study, 167 acral lesions (66 melanomas) were evaluated for 13 dermoscopic patterns by 26 physicians, via a secured Internet platform. RESULTS: Parallel furrow pattern, bizarre pattern, and diffuse pigmentation with variable shades of brown had the highest prevalence. The agreement for lesion patterns between physicians was variable. Agreement was dependent on the level of diagnostic difficulty. CONCLUSION: Lesions with a diameter >1 cm were more likely to be melanoma. We found as well that a benign pattern can be seen in parts of melanomas. For this reason one should evaluate an acral lesion for the presence of malignant patterns first.

Clinical and dermoscopic features of small Reed nevus (<6 mm).

BACKGROUND: The differential diagnosis between Reed nevi and melanoma becomes more difficult if the lesion to analyse presents a small size, with a diameter of 6 mm or smaller. Many studies have reported various dermoscopic features of Reed nevi during their growth phases. In early stages of evolution, the lesions generally show a characteristic globular appearance typically found in childhood, followed by the so-called starburst pattern. OBJECTIVE: The aim of the study was to identify the main dermoscopic features in small Reed nevi (<6 mm in size). METHODS: Using a computerized skin-imaging database for melanoma prevention surgery at the Department of Dermatology of the University of Florence, 15 Reed nevi were selected among 103 small (<6 mm) melanocytic lesions consecutively excised. Images of small Reed nevi, independently blinded to histopathological diagnosis, were administered to a dermatologist expert in dermoscopy, who separately examined the clinical and the dermatoscopic images of small Reed nevi and evaluated their clinical and dermoscopic parameters. RESULTS: Analysis of the main dermoscopic patterns showed that 40% had a reticular pattern, 20% had a starburst pattern, 6.5% had a globular pattern, 6.5% had a homogeneous pattern and 27% had an atypical pattern. CONCLUSION: We propose that small, early-stage Reed nevus are not characterized by an evolution of growth patterns to a phenotype typical of larger lesions. We assume that the patterns are distributed in a linear manner between age groups, may all be present at the outset and thus are independent from the various stages of nevus development.

RECURRENT LENTIGO MALIGNA: CONSERVATIVE CONTINUOUS TREATMENT WITH IMIQUIMOD OR REPEATED SURGERY? A LONG-TERM FOLLOW-UP DERMOSCOPIC CASE STUDY.

A case of recurrent lentigo maligna in a 45-year-old woman is presented. The disease relapsed several times following the surgical excision of the lesion. An alternative treatment with imiquimod 5% cream was then used. After 4 years of follow-upfrom the last surgery, this treatment achieved total clearance of the lesion. The problems of lentigo maligna diagnosis and treatment are discussed.

Guidelines for the diagnosis and treatment of basal cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care.