Imma Savarese

Cutaneous manifestations of breast carcinoma.

The incidence of breast carcinoma cutaneous manifestation in patients with breast carcinoma is 23.9%. The most common sites of breast carcinoma cutaneous manifestation are the chest wall and abdomen, but they can occur at the extremities and in the head/neck region. Due the high incidence of breast carcinoma, these cutaneous manifestations are the most common metastases seen by dermatologists.

The prognostic impact of the anatomical sites in the 'head and neck melanoma': scalp versus face and neck.

Cutaneous melanoma is a malignant neoplasia with several demographic and histopathological prognostic factors. Many studies stress that the head and neck region has a worse prognosis compared with other localizations, but the reasons for this worse prognosis are unclear. Therefore, the aim of our study is to analyse the poor prognosis of head and neck melanoma (HNM) with respect to the other anatomical sites, considering the face and neck (F&N) and the scalp separately. We carried out a retrospective analysis of 757 melanoma patients. In particular, we studied the prognostic impact of different melanoma skin localizations (head and neck, trunk, upper extremities and lower extremities). Afterwards, we divided HNM into two subgroups, F&N and scalp, to evaluate their impact in the HNM prognosis. Data showed a significantly lower 5-year overall survival probability for HNM (78.9 versus 93.1% for other body sites; P=0.05). Moreover, on analysing the two anatomical areas considered among HNM, we observed a 5-year overall survival of 81.8% for F&N and 66.7% for scalp. HNM has different and worse prognostic features with respect to other sites, but this trend is not only because of scalp melanoma but is also determined by F&N melanoma, which we believe to be underestimated until now.

Is skin self-examination for cutaneous melanoma detection still adequate? A retrospective study.

Objective: The aim of this retrospective study was to analyze the relationship between detection pattern, tumor thickness, patient demographics, and personal and family history of melanoma in the era of noninvasive diagnosis. Methods: All patients with primary cutaneous melanoma who presented to the Department of Dermatology at the University of Florence between January 2000 and November 2010 were interviewed at the time of their final histopathological diagnoses of melanoma as part of their clinical record. The treating physician specifically questioned all patients about who had first detected or suspected the lesion that resulted in the histological diagnosis of melanoma. Results: A total of 802 melanoma patients were analyzed. The spouse found approximately 16% of the melanomas, and a similar percentage was discovered by the general practitioner. The largest group of melanomas (36%) was discovered during regular annual skin examinations by dermatologists, while another large group (33%) were discovered by the patients themselves. The data that emerged from our study is that self-detection was associated with a greater probability of having a thick melanoma and, therefore, a poor prognosis (odds ratio 1.56). Conclusions: Because the current mortality of melanoma is still stable, we are convinced that a new message should be introduced to encourage high-risk patients to have an annual skin examination as a rule.

Features of small melanocytic lesions: does small mean benign? A clinical–dermoscopic study

The use of dermoscopy is known to increase the sensitivity and specificity in the clinical diagnosis of cutaneous pigmented melanocytic lesions compared with naked-eye examinations. However, small pigmented melanocytic lesions with maximum clinical diameters of 6 mm remain the most significant diagnostic challenge to the clinician, particularly in the diagnosis of small melanoma, both in naked-eye and in dermatoscopic examinations. The aim of the present study was to analyze the clinical and dermatoscopic features of small pigmented melanocytic lesions, focusing on more frequently occurring features in small melanoma to identify them earlier. A total of 103 pigmented melanocytic lesions with diameters less than 6 mm were analyzed. On histopathological examination, 34 of these lesions were diagnosed as melanomas and the remaining lesions (n=69) were diagnosed as benign, melanocytic lesions. Images of cases were independently and blindly administered to three dermatologist experts in dermoscopy, who were asked to examine the clinical and dermatoscopic images of melanocytic skin lesions separately and to fill out a printed questionnaire to rate the images according to the ABCD clinical criteria and according to typical dermoscopic pattern analyses. The results of the questionnaires were then analyzed and crossed in order to rate the clinical and dermoscopic features of small pigmented lesions. Our study proved that the clinical criteria for diagnosing melanoma are not as reliable in the diagnosis of pigmented lesions of less than 6 mm diameter. However, the use of dermoscopy, even if not nullifying, allows a better classification of small, melanocytic lesions through pattern analysis.

Sun exposure and children: what do they know? An observational study in an Italian school.

Melanoma, the most aggressive skin tumor, is very rare in subjects younger than 20 years of age, representing 1–3% of all malignancies (Bader et al., 1985; Boddie et al., 1978;Gibbs et al., 2000;Handfield-Jones and Smith, 1996; Ruiz-Maldonado andOrozco-Covarrubias, 1997; Saenz et al., 1999). Despite its rarity, recent studies report that the occurrence ofmelanoma in early life is increasing (Oliveria et al., 2009; Strouse et al., 2005). The incidence of malignant melanoma (MM) in people aged b20 years increased 2.9% per year from 1973 to 2001 (Mones and Ackerman, 2003). Understanding the cause of this rising incidence may have a significant impact on the primary prevention of melanoma, but it is difficult to determine the exact cause because several factors, both constitutional and environmental, affect the development of atypical nevi andMM in early life. There are discordant data regarding the impact of sun-protective behaviors on melanoma prevention, but this discordance might be the result of the use of nonstandardized measures and strategies for the control of confounding factors. It is well known that sunburns early in life increase a persons risk for melanoma later in life; therefore, we investigated childrens awareness and knowledge regarding sunexposure and relevantbehaviors.We report baseline results of an observational study in 11to 16year-old school children, completed for the first time, to our knowledge, in Italy. The study was conducted among children from a Florentine public school. Children were asked to complete a self-administered questionnaire regarding sun-protection practices and sun exposure. The questionnaire included 10 items that had been formulated by experienced dermatologists based on the most common mistakes and misconceptions about the sun exposure (Table 1). A total of 379 student surveys were collected. The mean (SD) age was 12.59 (1.06)years (range 11–16 years). Males slightly outnumbered females (194, 51.2% for males versus 185, 48.8% for females). The student responses to the questionnaire items were used for the analysis. Overall, we counted 16 (4.8%) missing responses. The majority of subjects (346, 91.3%) told us to apply a sunscreen, but only half (191, 50.4%) of the students put on sunblock several times during the day and repeated the application after bathing. It is interesting to highlight that up to 80% of the students declared that they protected their skin with sunblock or clothing evenwhen under an umbrella or on cloudy summer days. The old misconception that a bleeding mole, previously traumatized, is dangerous persists even in the new generations (313, 82.6%). Despite the ‘indicted’ andwidespread adolescent use of tanning beds, only 17 students (4.5%) admitted to using artificial tanning. Less than 10% of subjects believed that artificial tanning is no

Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup

BACKGROUND Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral. OBJECTIVE We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history. METHODS In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor. RESULTS CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether. LIMITATIONS The study was hospital based, not population based. Rare novel susceptibility genes were not tested. CONCLUSION Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.

Obesity and melanoma.

MADAM, Shipman and Millington have properly explored the association of obesity, the biggest health problem of our times, with skin diseases. Because of the worldwide increasing incidence of malignant melanoma (MM), in oncology research, increasing attention has been focused on the potential role of changing lifestyle factors, particularly with obesity and diet. Although, as stated by the authors, the links between obesity and melanoma remain largely unexplored, population-based epidemiological studies have lately emerged providing plausible evidence for a link between obesity and MM. Brandon et al. found that obesity causes rapid melanoma growth by promoting angiogenesis in obese mice. Mechanisms that link excess weight and cancer risk are not fully understood and are still more unclear in MM than in other neoplasms. The authors have mentioned the leptin pathway without elucidating the biological basis of such a relationship. At least four different mechanisms seem to be involved in the association between excess body weight and MM risk. Firstly, obesity provides multiple hormonal and metabolic changes through three hormone systems, including the insulin and insulin-like growth factor (IGF) axis, sex steroids and adipokines. Chronic hyperinsulinaemia, a consequence of insulin resistance in the obese, increases IGF-1 bioavailability, which, in turn, favours tumour growth by inhibiting apoptosis and stimulating cell proliferation in the so-called insulin-cancer hypothesis. In this regard, hyperglycaemia, independently from body mass index (BMI), has been associated with a twofold increase of MM risk. With regard to the relationship between obesity and sex steroids, hyperinsulinaemia and elevated IGF-1 result in reduced hepatic synthesis of sex hormone-binding globulin (SHBG), therefore allowing greater bioavailability of free oestrogen. In addition, among overweight individuals there is an increased peripheral conversion of androgens to oestrogens in fat tissue. Thus, given that the presence of oestrogen receptors in melanocytes has been demonstrated, we cannot rule out that increased plasma oestrogen levels in obese individuals might contribute to enhance tumour growth in MM, as already observed in breast cancer. Secondly, leptin, an insulin-sensitizing adipokine which is produced mainly from visceral fat adipocytes in proportion to the mass of adipose tissue, causes inflammation, cell proliferation and angiogenesis. In MM, leptin accelerates in vivo tumour growth and increases tumour angiogenesis by interacting with angiogenic factors, such as vascular endothelial growth factor (VEGF), which are upregulated in MMs from obese mice. Moreover, MM risk was found to be positively associated with serum leptin levels in a recent epidemiological study. Thirdly, caveolin-1 (Cav-1), a protein involved in the organization and remodelling of the extracellular matrix, has been directly correlated with tumour growth, aggressiveness and progression of MM. Recently, a study has clearly evidenced that Cav-1 expression is significantly influenced in vivo by diet-induced obesity. Fourthly, BMI is inversely associated with serum vitamin D levels, which are related with MM risk and outcome. Indeed, lower serum 25(OH)D3 levels were found in patients with MM compared with the control group. Furthermore, higher serum 25(OH)D3 levels, at MM diagnosis, were associated with both thinner lesions and better survival from MM, suggesting a role for vitamin D in MM outcome. Finally, further plausible carcinogenic mechanisms of obesity include long-term storage of toxins, medications and vitamins in adipose tissue, which can serve as a continuous source of carcinogens. Therefore, the pathophysiology of obesity is complex and multifactorial, and thus, it is unlikely that ‘one size fits all’. We believe that all these mechanisms can coexist and play not mutually exclusive functions in increasing MM risk among obese individuals. If obesity is going to be consistently reported as a modifiable risk factor for MM, given the high prevalence of obesity in developed countries, more intervention research on the prevention and treatment of obesity may be another essential component of future research in primary prevention of melanoma, having a strong impact on MM diagnosis and prognosis.

Adding dermatoscopy to naked eye examination of equivocal melanocytic skin lesions: effect on intention to excise by general dermatologists

Background.  According to the literature, dermatoscopy can improve diagnostic accuracy for melanoma. However, a weak point of the studies in the literature is that most were carried out in a ‘privileged’ setting of dermatologists who are expert in dermato‐oncology, and who work in departments specializing in screening pigmented lesions. This study was set up to specifically evaluate whether the use of dermatoscopy by general dermatologists would also improve accuracy.

Skin self‐examination and the ABCDE rule in the early diagnosis of melanoma: is the game over?

1 de Paiva A, Meunier FA, Molgó J et al. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci USA 1999; 96:3200–5. 2 Nakamizo S, Egawa G, Miyachi Y, Kabashima K. Cholinergic urticaria: pathogenesis-based categorization and its treatment options. J Eur Acad Dermatol Venereol 2012; 26:114–16. 3 Duke WW. Urticaria caused specifically by the action of physical agents. JAMA 1924; 83:3–9. 4 Shelley WB, Shelley ED, Ho AK. Cholinergic urticaria: acetylcholine-receptor-dependent immediate-type hypersensitivity reaction to copper. Lancet 1983; 1:843–6. 5 Adachi J, Aoki T, Yamatodani A. Demonstration of sweat allergy in cholinergic urticaria. J Dermatol Sci 1994; 7:142–9. 6 Itakura E, Urabe K, Yasumoto S et al. Cholinergic urticaria associated with acquired generalized hypohidrosis: report of a case and review of the literature. Br J Dermatol 2000; 143:1064–6. 7 Sawada Y, Nakamura M, Bito T et al. Cholinergic urticaria: studies on the muscarinic cholinergic receptor M3 in anhidrotic and hypohidrotic skin. J Invest Dermatol 2010; 130:2683–6. 8 Bito T, Sawada Y, Tokura Y. Pathogenesis of cholinergic urticaria in relation to sweating. Allergol Int 2012; 61:539–44.

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

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.