Lentigo maligna of the face: A quantitative simple method to identify individual patient risk probability on dermoscopy.

BACKGROUND/OBJECTIVES: The clinical and dermoscopic differential diagnosis of flat pigmented facial lesions represents a great challenge for the clinicians. Our aim was to report a quantitative method based on dermoscopic features to better classify pigmented facial lesions. METHODS: This is a retrospective case-series study that analysed the dermoscopic features of 582 pigmented facial lesions. RESULTS: The individual patient probability of lentigo maligna (LM) was predicted by a multivariate model, with an accuracy of 0.72. According to the odds ratio at the multivariate analysis, an individual scoring index was assigned to each criterion, and a value of 4.56 was identified as optimal cut-off point. Up to a score of 2.5, the probability that a lesion is an LM is 0. The probability increases from 10 to 50% for a score ranging between 4.5 and 6. It is about 90% for a score of 7. CONCLUSION: The optimal cut-off point obtained and the curve that identifies the probability of a patient having a LM could improve the classification and the management strategies of equivocal pigmented facial lesions.

Can video thermography improve differential diagnosis and therapy between basal cell carcinoma and actinic keratosis?

Various noninvasive techniques (dermoscopy, confocal microscopy, etc.) have been introduced to help the clinical diagnosis in nonmelanoma skin cancer. Among them, the high definition video thermographic technique (VTG) has recently been proposed. The aim of this study is to define the VTG patterns, respectively of actinic keratosis (AK) and basal cell carcinoma (BCC), and to compare these data with them of dermoscopy. The study included 36 patients with a total number of 135 lesions who underwent clinical, VTG, and dermoscopic examination. The VTG showed the presence of a hyperthermic pattern in all the cases of AK, while in the case of the BCC, the pattern was hypothermic. Dermoscopy also showed distinct pattern for AK and for BCC, but in 22% of them the data were not conclusive. Our study permits us to define two specific VTG patterns, BCC and AK respectively.

Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants.

BACKGROUND: CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. METHODS: All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. RESULTS: Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). CONCLUSION: Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.

Dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squamous cell carcinoma: a progression model.

BACKGROUND: Little is known about the dermoscopic features of keratinocyte skin cancer. OBJECTIVE: We sought to determine the dermoscopic features of facial actinic keratosis (AK), intraepidermal carcinoma (IEC), moderately to poorly differentiated invasive squamous cell carcinoma (SCC), and well-differentiated SCC of the keratoacanthoma type. METHODS: This was a retrospective analysis of dermoscopic images of histopathologically diagnosed keratinocyte skin cancer. RESULTS: A total of 243 (70 AK, 71 IEC, 78 SCC, and 24 keratoacanthomas) tumors of the face from 243 patients (mean age: 71.1 years; range: 44-94 years) were analyzed. The majority of patients had a fair skin type, history of melanoma or nonmelanoma skin cancer, and multiple AK. A red pseudonetwork was significantly associated with AK (P < .001), whereas dotted/glomerular vessels, diffuse yellow opaque scales, and microerosions were significantly more prevalent among IEC (P < .001). Hairpin vessels, linear-irregular vessels, targetoid hair follicles, white structureless areas, a central mass of keratin, and ulceration were significantly associated with invasive SCC (P < .001 for all criteria). Similar patterns as in SCC were observed among keratoacanthomas. LIMITATIONS: The retrospective design of our study and the lack of assessment of sensitivity and specificity of the dermoscopic criteria are limitations. CONCLUSIONS: Based on our findings we propose a progression model of facial AK developing into IEC and invasive SCC.

Total body skin examination for skin cancer screening in patients with focused symptoms.

BACKGROUND: The value of total body skin examination (TBSE) for skin cancer screening is controversial. OBJECTIVE: We sought to determine whether TBSE could be helpful in patients with focused skin symptoms who would not otherwise have undergone TBSE. METHODS: In a prospective, multicenter, cross-sectional study consecutive adult patients were recruited during a period of 18 months. Physicians first inspected problem areas and uncovered areas and then performed TBSE. Equivocal lesions detected in both steps were excised or biopsied. Primary outcomes were the absolute and relative risks of missing skin cancer and the number of patients needed to examine to detect melanoma or another malignancy. A secondary outcome was the proportion of false-positive results obtained by TBSE. RESULTS: We examined 14,381 patients and detected 40 (0.3%) patients with melanoma and 299 (2.1%) with at least one nonmelanoma skin cancer by TBSE. In 195 (1.3%) patients equivocal lesions found by TBSE turned out to be benign. We calculated that 47 patients need to be examined by TBSE to find one skin malignancy and 400 patients to detect one melanoma. The risk of missing one malignancy if not performing TBSE was 2.17% (95% confidence interval 1.25-3.74). Factors significantly increasing the chance to find a skin cancer were age, male gender, previous nonmelanoma skin cancer, fair skin type, skin tumor as the reason for consultation, and presence of an equivocal lesion on problem/uncovered areas. LIMITATIONS: The impact of TBSE on skin cancer mortality was not evaluated. CONCLUSIONS: TBSE improves skin cancer detection in patients with focused skin symptoms and shows a low rate of false-positive results.

Reflectance confocal microscopy for the evaluation of solitary red nodules.

The correct assessment of a solitary red nodule in clinical practice is of crucial importance, amelanotic melanoma being the most important differential diagnosis. Dermoscopy is nowadays a pivotal tool in the management of skin tumors, however it has some limitations in the evaluation of nonpigmented lesions, in which the diagnosis is merely based on the evaluation of the vascular pattern. Recently, reflectance confocal microscopy has been introduced as a new, noninvasive technique for the diagnosis of skin lesions. Confocal microscopy provides skin imaging in vivo at cellular level resolution, close to conventional histology. We present a series of clinical scenarios of red nodules, including melanoma metastasis, pyogenic granuloma, eccrine poroma, Spitz nevus and dermatofibroma. Reflectance confocal microscopy examination added important information to the clinical diagnosis and subsequent management in all cases except for dermatofibroma. We discuss the advantages and limitations of this technique in this particular field of application.

Dermoscopy of pigmented lesions of the vulva: a retrospective morphological study.

BACKGROUND: The dermoscopic patterns of pigmented skin tumors are influenced by the body site. OBJECTIVE: To evaluate the clinical and dermoscopic features associated with pigmented vulvar lesions. METHODS: Retrospective analysis of clinical and dermoscopic images of vulvar lesions. The χ² test was used to test the association between clinical data and histopathological diagnosis. RESULTS: A total of 42 (32.8%) melanocytic and 86 (67.2%) nonmelanocytic vulvar lesions were analyzed. Nevi significantly prevailed in younger women compared with melanomas and melanosis and exhibited most commonly a globular/cobblestone (51.3%) and a mixed (21.6%) pattern. Dermoscopically all melanomas showed a multicomponent pattern. Melanotic macules showed clinical overlapping features with melanoma, but their dermoscopic patterns differed significantly from those observed in melanomas. CONCLUSION: The diagnosis and management of pigmented vulvar lesions should be based on a good clinicodermoscopic correlation. Dermoscopy may be helpful in the differentiation of solitary melanotic macules from early melanoma.

[Skin cancer risk factors in childhood: findings of a survey conducted within Italian areas with a different incidence of melanoma]. / Infanzia e fattori di rischio per tumori della cute: risultati di un indagine in aree italiane a diversa incidenza di melanoma cutaneo.

OBJECTIVE: to evaluate the association between phenotype and sun sensitivity factors, sun protection behavior, ethnicity and the area of residence in school-aged children. DESIGN: a cross-sectional study in the framework of a survey of children using a self-administered questionnaire to be filled in by parents. SETTING AND PARTICIPANTS: 56390 children attending primary schools located in the Italian provinces of Brindisi, Rome, Forlì and Genova, in the period between 1998-2002. MAIN OUTCOME MEASURES: Odds Ratios (ORs) and their relative 95% Confidence Intervals (95% CI) are to be computed through univariate and multivariate logistic regression models. RESULTS: "FOTO positive" phenotype, a proxy variable of the fair phenotype, was directly and significantly associated with the tendency to sunburn (OR 4.75; 95% CI 4.54-4.96), the use of sunscreens (OR 1.79; 95% CI 1.63-1.97), the number of grandparents born in the northern areas (OR 1.63; 95% CI 1.45-1.83, for four northern grandparents versus none), the presence of freckles on the face (OR 1.62; 95% CI 1.53-1.72) and of naevi on the left forearm (OR 1.20; 95% CI 1.15-1.26). A positive association was also found for the residence in the northern areas using the area of Brindisi as the reference category, (Rome: OR 1.02; 95% CI 0.95-1.10; Forlì: OR 1.05; 95% CI 0.96-1.15; Genova: OR 1.16; 95% CI 1.08-1.26); the ORs increase with latitude, as does the incidence rate of melanoma in Italy. An inverse association was observed with the male sex (OR 0.92; 95% CI 0.88-0.96), the increase of school-class level (OR 0.65; 95% CI 0.60-0.69, for the highest versus the lowest school-class level) and the ability to tan (OR 0.40; 95% CI 0.36-0.43). CONCLUSION: these findings confirmed that the fairness phenotype is associated with other skin cancer risk factors in children and pointed out that the high-risk phenotype has a geographical distribution consistent with the pattern of melanoma incidence in the Italian areas covered by the study.

Cathepsin B inhibition interferes with metastatic potential of human melanoma: an in vitro and in vivo study.

BACKGROUND: Cathepsins represent a group of proteases involved in determining the metastatic potential of cancer cells. Among these are cysteinyl- (e.g. cathepsin B and cathepsin L) and aspartyl-proteases (e.g. cathepsin D), normally present inside the lysosomes as inactive proenzymes. Once released in the extracellular space, cathepsins contribute to metastatic potential by facilitating cell migration and invasiveness. RESULTS: In the present work we first evaluated, by in vitro procedures, the role of cathepsins B, L and D, in the remodeling, spreading and invasiveness of eight different cell lines: four primary and four metastatic melanoma cell lines. Among these, we considered two cell lines derived from a primary cutaneous melanoma and from a supraclavicular lymph node metastasis of the same patient. To this purpose, the effects of specific chemical inhibitors of these proteases, i.e. CA-074 and CA-074Me for cathepsin B, Cathepsin inhibitor II for cathepsin L, and Pepstatin A for cathepsin D, were evaluated. In addition, we also analyzed the effects of the biological inhibitors of these cathepsins, i.e. specific antibodies, on cell invasiveness. We found that i) cathepsin B, but not cathepsins L and D, was highly expressed at the surface of metastatic but not of primary melanoma cell lines and that ii) CA-074, or specific antibodies to cathepsin B, hindered metastatic cell spreading and dissemination, whereas neither chemical nor biological inhibitors of cathepsins D and L had significant effects. Accordingly, in vivo studies, i.e. in murine xenografts, demonstrated that CA-074 significantly reduced human melanoma growth and the number of artificial lung metastases. CONCLUSIONS: These results suggest a reappraisal of the use of cathepsin B inhibitors (either chemical or biological) as innovative strategy in the management of metastatic melanoma disease.

How to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part I. Melanocytic skin tumors.

Dermoscopy is a noninvasive tool that can be helpful in the diagnosis of nonpigmented skin tumors. This is because dermoscopy permits the visualization of key vascular structures that are usually not visible to the naked eye. Much work has concentrated on the identification of specific morphologic types of vessels that allow a classification into melanocytic versus nonmelanocytic and benign versus malignant nonpigmented skin tumors. Among a broad spectrum of different types of vascular patterns, six main morphologies can be identified. These are comma-like, dotted, linear-irregular, hairpin, glomerular, and arborizing vessels. With some exceptions, comma, dotted, and linear irregular vessels are associated with melanocytic tumors, while the latter three vascular types are generally indicative of keratinocytic tumors. Aside from vascular morphology, the architectural arrangement of vessels within the tumor and the presence of additional dermoscopic clues are equally important for the diagnosis. This article provides a general overview of the dermoscopic evaluation of nonpigmented skin tumors and is divided into two parts. Part I discusses the dermoscopic vascular patterns of benign and malignant melanocytic skin tumors. Part II discusses the dermoscopic vascular patterns of benign and malignant nonmelanocytic nonpigmented skin tumors. In each part, additional special management guidelines for melanocytic and nonmelanocytic nonpigmented skin tumors, respectively, will be discussed.

How to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part II. Nonmelanocytic skin tumors.

Nonmelanoma skin cancer refers to a broad class of tumors, including actinic keratosis, basal cell carcinoma, and squamous cell carcinoma, and as a group these are the most frequent cancers occurring in light skinned humans. In contrast to the rarity of amelanotic melanoma, nonmelanoma skin cancer commonly lacks pigmentation. Although these tumors rarely cause death related to metastases, they commonly destroy underlying tissues and should be removed at the earliest possible stage. Dermoscopy improves the clinical diagnosis of nonpigmented skin tumors by allowing the visualization of specific vascular structures that are usually not visible to the naked eye. Dermoscopic vascular patterns of several nonmelanocytic nonpigmented skin tumors, such as sebaceous hyperplasia, seborrheic keratosis, clear cell acanthoma, Bowen disease, or nodular cystic basal cell carcinoma are highly specific, allowing a ready diagnosis in most cases. Others, such as actinic keratosis, pyogenic granuloma, or uncommon adnexal tumors, may be difficult to differentiate even with the aid of dermoscopy. For this reason, general guidelines have been established to assist in making the most appropriate management decision. In the second part of this review of dermoscopic vascular structures of nonpigmented skin tumors, the dermoscopic patterns associated with benign and malignant nonmelanocytic skin tumors and recommendations for the management of these tumors will be discussed.

Dermoscopy of cutaneous sarcoidosis.

BACKGROUND: The clinical variability of cutaneous sarcoidosis (CS) often makes its correct diagnosis challenging. Although traditionally employed for the diagnosis of skin tumors, during the past years dermoscopy also gained increasing interest as an aid in the clinical diagnosis of inflammatory and infectious skin manifestations in general dermatology. OBJECTIVE: Our purpose was to evaluate the usefulness of dermoscopy in the differential diagnosis of CS. METHODS: This was a retrospective analysis of 7 clinical and dermoscopic images of CS that were collected at dermatology clinics in France and Italy between 2005 and 2009. RESULTS: Retrospective dermoscopic evaluation revealed small grouped, translucent orange globular structures associated with linear vessels of variable diameter in all 7 cases. In 5 cases, additional central scar-like areas were seen. CONCLUSION: Lesions showing dermoscopically translucent yellow to orange globular-like or structureless areas associated with linear vessels should raise the suspicion of a granulomatous skin disease, including CS.

Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study.

Clinical studies based on novel rationales and mechanisms of action of chemotherapy agents and cytokines can contribute to the development of new concepts and strategies of antitumor combination therapies. In previous studies, we investigated the paradoxical immunostimulating effects of some chemotherapeutics and the immunoadjuvant activity of interferon alpha (IFN-α) in preclinical and clinical models, thus unraveling novel rationales and mechanisms of action of chemotherapy agents and cytokines for cancer immunotherapy. Here, we carried out a randomized, phase II clinical trial, in which we analyzed the relapse-free (RFS) and overall survival (OS) of 34 completely resected stage III-IV melanoma patients, treated with peptide-based vaccination (Melan-A/MART-1 and NY-ESO-1) in combination with IFN-α2b, with (arm 2) or without (arm 1) dacarbazine preconditioning. All patients were included in the intention-to-treat analysis. At a median follow-up of 4.5 years (interquartile range, 15.4-81.0 months), the rates of RFS were 52.9 and 35.3% in arms 1 and 2, respectively. The 4.5-year OS rates were 68.8% in arm 1 and 62.7% in arm 2. No significant differences were observed between the two arms for both RFS and OS. Interestingly, the RFS and OS curves remained stable starting from 18 and 42 months, respectively. Grade 3 adverse events occurred in 5.9% of patients, whereas grade 4 events were not observed. Both treatments induced a significant expansion of vaccine-specific CD8+ T cells, with no correlation with the clinical outcome. However, treatment-induced increase of polyfunctionality and of interleukin 2 production by Melan-A-specific CD8+ T cells and expansion/activation of natural killer cells correlated with RFS, being observed only in nonrelapsing patients. Despite the recent availability of different therapeutic options, low-cost, low-toxic therapies with long-lasting clinical effects are still needed in patients with high-risk resected stage III/IV melanoma. The combination of peptide vaccination with IFN-α2b showed a minimal toxicity profile and resulted in encouraging RFS and OS rates, justifying further evaluation in clinical trials, which may include the use of checkpoint inhibitors to further expand the antitumor immune response and the clinical outcome. Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/search, identifier: 2008-008211-26.

Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients.

Combination of chemotherapy with cancer vaccines is currently regarded as a potentially valuable therapeutic approach for the treatment of some metastatic tumors, but optimal modalities remain unknown. We designed a phase I/II pilot study for evaluating the effects of dacarbazine (DTIC) on the immune response in HLA-A2(+) disease-free melanoma patients who received anticancer vaccination 1 day following chemotherapy (800 mg/mq i.v.). The vaccine, consisting of a combination of HLA-A2 restricted melanoma antigen A (Melan-A/MART-1) and gp100 analog peptides (250 microg each, i.d.), was administered in combination or not with DTIC to 2 patient groups. The combined treatment is nontoxic. The comparative immune monitoring demonstrates that patients receiving DTIC 1 day before the vaccination have a significantly improved long-lasting memory CD8(+) T cell response. Of relevance, these CD8(+) T cells recognize and lyse HLA-A2(+)/Melan-A(+) tumor cell lines. Global transcriptional analysis of peripheral blood mononuclear cells (PBMC) revealed a DTIC-induced activation of genes involved in cytokine production, leukocyte activation, immune response and cell motility that can favorably condition tumor antigen-specific CD8(+) T cell responses. This study represents a proof in humans of a chemotherapy-induced enhancement of CD8(+) memory T cell response to cancer vaccines, which opens new opportunities to design novel effective combined therapies improving cancer vaccination effectiveness.

Angiomatous reaction Kaposi-sarcoma-like as a side effect of topical corticosteroid therapy in lichen sclerosus of the penis.

Lichen sclerosus (LS) is a chronic inflammatory skin condition usually located in the anogenital area. Topical corticosteroid therapy is the first choice treatment which may arrest or delay the progression of the disorder. We report the case of a 74-year-old man presented with a 6-month history of nodular lesions localized on penis. The man had a previous history of genital lesions that had been diagnosed as LS and treated with long-term topical corticosteroid therapy. After 3 months of corticosteroid therapy, the patient observed the appearance of several nodular erythematous lesions on the penis with progressive disappearance of the clinical symptoms of LS. These purple to red asymptomatic angiomatoid nodules resembled the clinical features of Kaposi sarcoma.

[Skin cancer risk factors in childhood: findings of a survey in an Italian area characterized by atypical migration]. / Infanzia e fattori di rischio per tumori della cute: risultati di un'indagine in un'area italiana oggetto di una migrazione atipica.

OBJECTIVE: to evaluate the association of different phenotypes with sun sensitivity factors, sun protection behavior and ethnicity in school-age children. DESIGN: cross sectional study in the framework of a survey of children using a self-administered questionnaire. SETTING AND PARTICIPANTS: 35412 children attending primary schools in the provinces of Latina and Rome, located in the Lazio region (Italy), in the 1998-2001 time period. MAIN OUTCOME MEASURES: Odds Ratios (ORs) and their relative 95% Confidence Intervals (95% CI) computed through univariate and multivariate logistic regression models. RESULTS: "FOTO positive" phenotype, a proxy variable of the fair phenotype, was directly and significantly associated with the tendency to sunburn (OR 4.64; 95% CI 4.39-4.89), the presence of freckles on the face (OR 1.65; 95% CI 1.55-1.77), of naevi on the left forearm (OR 1.18; 95% CI 1.12-1.25), the number of grandparents born in northern areas (OR 1.54; 95% CI 1.15-2.07, for four northern grandparents versus none), the residence in Latina Province (OR 1.13; 95% CI 1.07-1.20) and the use of sunscreens (OR 1.70; 95% CI 1.55-1.88). An inverse association was observed with the male sex (OR 0.91; 95% CI 0.86-0.96), the increase of school-class level (OR 0.66; 95% CI 0.61-0.72, for the highest versus the lowest school-class level) and the ability to tan (OR 0.38; 95% CI 0.34-0.42). CONCLUSION: These findings confirmed that fairness of phenotype is associated in children with other skin cancer risk factors as well as ethnicity and parents' sun protection behavior.

Insulin-like growth factor I (CA) repeats are associated with higher melanoma's Breslow index but not associated with the presence of the melanoma. A pilot study.

BACKGROUND: IGF-I-(CA) repeats have been previously analysed in few types of cancer and the results, although discordant in different studies, showed possible associations between cancer and IGF-I(CA)(19) repeats. Aim of this pilot study was to detect a possible association between some of the IGF-I(CA) repeats and the presence of malignant melanoma and its Breslow index. METHODS: Two hundred patients affected with cutaneous malignant melanoma and 100 control healthy subjects were analysed for IGF-I(CA) repeats by fragment analysis sequencing and, partially, confirmed by direct sequencing. RESULTS: A significant association of IGF-I(CA)(19) repeats was observed with melanoma higher Breslow indices (P<0.001), while no association between melanoma patients and the different genotypes of IGF-I(CA) was found. The above mentioned association was confirmed after Bonferroni's correction for multiple comparisons and also by logistic regression analysis adjusted for age, sex and BMI variables. A slight, significant difference (P=0.03) was observed for serum IGF-I values in IGF-I(CA)(19)-positive or IGF-I(CA)(19)-negative subjects. DISCUSSION: The association observed for IGF-I(CA)(19) and malignant melanoma is in keeping with similar results obtained in prostate or breast cancers, suggesting that this type of repeat may be directly or indirectly important in controlling cancer induction and its severity.

Vulvar melanoma: a report of 10 cases and review of the literature.

Despite its low incidence, vulvar melanoma carries a poor prognosis and shows a high tendency to metastasize because the diagnosis is often delayed. Although it is very well known that ultraviolet radiation is an important aetiological factor for cutaneous melanomas in adults, this cannot be considered true for vulvar melanoma. Chronic inflammatory disease, viral infections, irritant agents are the main factors suspected to induce mucosal melanoma. We report 10 cases of vulvar malignant melanoma observed in our institute from 1990 to 2005 and a review of the literature.