Ignazio Stanganelli

Dermoscopic Evaluation of Amelanotic and Hypomelanotic Melanoma

OBJECTIVE To determine the predictive dermoscopic features of amelanotic and hypomelanotic melanoma. DESIGN A total of 105 melanomas (median Breslow thickness, 0.76 mm), 170 benign melanocytic lesions, and 222 nonmelanocytic lesions lacking significant pigment (amelanotic, partially pigmented, and light colored) were imaged using glass-plate dermoscopy devices and scored for 99 dermoscopic features. Diagnostic models were derived from and tested on independent randomly selected lesions. SETTING Predominantly hospital-based clinics from 5 continents. MAIN OUTCOME MEASURES Sensitivity, specificity, and odds ratios for individual features and models for the diagnosis of melanoma and malignancy. RESULTS The most significant negative predictors of melanoma were having multiple (>3) milialike cysts (odds ratio, 0.09; 95% confidence interval, 0.01-0.64), comma vessels with a regular distribution (0.10; 0.01-0.70), comma vessels as the predominant vessel type (0.16; 0.05-0.52), symmetrical pigmentation pattern (0.18; 0.09-0.39), irregular blue-gray globules (0.20; 0.05-0.87), and multiple blue-gray globules (0.28; 0.10-0.81). The most significant positive predictors were having a blue-white veil (odds ratio,13; 95% confidence interval, 3.9-40.0), scarlike depigmentation (4.4; 2.4-8.0), multiple blue-gray dots (3.5; 1.9-6.4), irregularly shaped depigmentation (3.3; 2.0-5.3), irregular brown dots/globules (3.2; 1.8-5.6), 5 to 6 colors (3.2; 1.6-6.3), and predominant central vessels (3.1; 1.6-6.0). A simple model distinguishing melanomas from all nonmelanomas had a sensitivity of 70% and a specificity of 56% in the test set. A model distinguishing all malignant lesions from benign lesions had a sensitivity of 96% and a specificity of 37%. Conclusion Although the diagnostic accuracy of dermoscopy for melanoma lacking significant pigment is inferior to that of more pigmented lesions, features distinguishing the former from benign lesions can be visualized on dermoscopic evaluation.

Accuracy in melanoma detection: A 10-year multicenter survey

BACKGROUND Early excision is the only strategy to reduce melanoma mortality, but unnecessary excision of benign lesions increases morbidity and healthcare costs. OBJECTIVE To assess accuracy in melanoma detection based on number-needed-to-excise (NNE) values over a 10-year period. METHODS Information was retrieved on all histopathologically confirmed cutaneous melanomas or melanocytic nevi that were excised between 1998 and 2007 at participating clinics. NNE values were calculated by dividing the total number of excised lesions by the number of melanomas. Analyses included changes in NNE over time, differences in NNE between specialized clinical settings (SCS) versus non-specialized clinical settings (NSCS), and patient factors influencing NNE. RESULTS The participating clinics contributed a total of 300,215 cases, including 17,172 melanomas and 283,043 melanocytic nevi. The overall NNE values achieved in SCS and NSCS in the 10-year period were 8.7 and 29.4, respectively. The NNE improved over time in SCS (from 12.8 to 6.8), but appeared unchanged in NSCS. Most of the effect on NNE in SCS was due to a greater number of excised melanomas. Higher NNE values were observed in patients younger than 40 years and for lesions located on the trunk. LIMITATIONS No data concerning the use of dermatoscopy and digital monitoring procedures were collected from the participating centers. CONCLUSION Over the 10-year study period, accuracy in melanoma detection improved only in specialized clinics maybe because of a larger use of new diagnostic techniques such as dermatoscopy.

Slow-growing melanoma: a dermoscopy follow-up study

Background  Recent evidence suggests that melanoma is a family of different tumours with varying abilities to grow and metastasize. Trends in melanoma epidemiology show a strong increase in the incidence of thin melanoma, with no corresponding increase in mortality or incidence of thick melanoma. We initially evaluated five cases and found that none had baseline features suggestive of melanoma; excision was performed based on slight changes visible only in side‐by‐side comparisons of dermoscopic images.

Intraobserver agreement in interpretation of digital epiluminescence microscopy

BACKGROUND Although a major problem with the classification of epiluminescence microscopy (ELM) findings is the lack of standard definitions, reproducibility of the criteria proposed has never been investigated. OBJECTIVES Our purposes were (1) to perform a review of four major published classifications to obtain a set of apparently well-defined ELM variables and descriptors and (2) to evaluate the ability of one of us to report consistently ELM findings in melanocytic lesions according to these criteria. METHODS Intraobserver agreement (with a set of 44 selected descriptors) between two readings of 150 digital ELM images was evaluated with the kappa (kappa) statistic. Subgroups of descriptors were compared for kappa value distribution. RESULTS The median kappa value for the whole series of descriptors was 0.66. Median kappa did not vary significantly among the four classification systems (kappa = 0.61 to 0.67). Agreement was significantly better as to the presence or absence of ELM findings (kappa range, 0.39 to 1.00; median kappa, 0.77) compared with agreement as to their distribution (kappa range, 0.10 to 0.79; median kappa, 0.47; p = 0.0007) and their width, thickness, and size (kappa range, 0.06 to 0.83; median kappa, 0.39; p = 0.0075). CONCLUSION Although nothing can be inferred from a single study, descriptors associated with low intraobserver agreement are likely to be inadequately defined.

Seasonal prevalence of digital epiluminescence microscopy patterns in acquired melanocytic nevi

BACKGROUND Available information of the effect of sun exposure on the biologic activity and morphologic characteristics of nevi is based on a few cross-sectional studies. According to these, nevi excised in summer show a higher mitotic count, a greater extent of the junctional component, and more frequent regression and inflammation. OBJECTIVE Our goals were to obtain data on the seasonal prevalence of digital epiluminescence microscopy (D-ELM) patterns in acquired melanocytic nevi (AMN) and to test the reliability of D-ELM as a substitute for histology in prospective studies of the morphologic response of AMN to sun exposure. METHODS Two independent series of AMN located on intermittently sun-exposed body sites and undergoing D-ELM in winter (n=121) and in summer (n=116) were compared for the prevalence of major ELM patterns. RESULTS Cases in the summer series showed a greater frequency of a broad and prominent pigment network; black dots with varied size, irregular distribution, and peripheral location; and peripheral depigmentation. CONCLUSION On the basis of known histologic correlates of D-ELM features, our findings were consistent with studies of seasonal histologic changes in AMN. D-ELM may be a useful tool in the prospective evaluation of effects of sun exposure on AMN morphology.

Skin Cancer Diagnosis With Reflectance Confocal Microscopy: Reproducibility of Feature Recognition and Accuracy of Diagnosis

IMPORTANCE Reflectance confocal microscopy (RCM) studies have been performed to identify criteria for diagnosis of skin neoplasms. However, RCM-based diagnosis is operator dependent. Hence, reproducibility of RCM criteria needs to be tested. OBJECTIVE To test interobserver reproducibility of recognition of previously published RCM descriptors and accuracy of RCM-based skin cancer diagnosis. DESIGN, SETTING, AND PARTICIPANTS Observational retrospective web-based study of a set of RCM images collected at a tertiary academic medical center. Nine dermatologists (6 of whom had ≥3 years of RCM experience) from 6 countries evaluated an RCM study set from 100 biopsy-proven lesions, including 55 melanocytic nevi, 20 melanomas, 15 basal cell carcinomas, 7 solar lentigines or seborrheic keratoses, and 3 actinic keratoses. Between June 15, 2010, and October 21, 2010, participanting dermatologists, blinded to histopathological diagnosis, evaluated 3 RCM mosaic images per lesion for the presence of predefined RCM descriptors. MAIN OUTCOMES AND MEASURES The main outcome was identification of RCM descriptors with fair to good interrater agreement (κ statistic, ≥0.3) and independent correlation with malignant vs benign diagnosis on discriminant analysis. Additional measures included sensitivity and specificity for diagnosis of malignant vs benign for each evaluator, for majority diagnosis (rendered by ≥5 of 9 evaluators), and for experienced vs recent RCM users. RESULTS Eight RCM descriptors showed fair to good reproducibility and were independently associated with a specific diagnosis. Of these, the presence of pagetoid cells, atypical cells at the dermal-epidermal junction, and irregular epidermal architecture were associated with melanoma. Aspecific junctional pattern, basaloid cords, and ulceration were associated with basal cell carcinomas. Ringed junctional pattern and dermal nests were associated with nevi. The mean sensitivity for the group of evaluators was 88.9% (range, 82.9%-100%), and the mean specificity was 79.3% (range, 69.2%-90.8%). Majority diagnosis showed sensitivity of 100% and specificity of 80.0%. Sensitivity was higher for experienced vs recent RCM users (91.0% vs. 84.8%), but specificity was similar (80.0% vs. 77.9%). CONCLUSIONS AND RELEVANCE The study highlights key RCM diagnostic criteria for melanoma and basal cell carcinoma that are reproducibly recognized among RCM users. Diagnostic accuracy increases with experience. The higher accuracy of majority diagnosis suggests that there is intrinsically more diagnostic information in RCM images than is currently used by individual evaluators.

A Cancer-Registry-Assisted Evaluation of the Accuracy of Digital Epiluminescence Microscopy Associated with Clinical Examination of Pigmented Skin Lesions

Background: The accuracy of digital epiluminescence microscopy (D-ELM) as an adjunct to clinical examination for the diagnosis of pigmented skin lesions (PSLs) has seldom been evaluated. Objective: To compare the accuracy of the combined clinical/D-ELM (C/D-ELM) examination with that of the clinical examination alone. Methods: A total of 3,372 PSLs from 1,556 consecutive patients referred to a skin cancer clinic underwent clinical examination and a combined C/D-ELM examination. The reference diagnosis was established using the histology report of known surgical excisions plus a cancer-registry-based follow-up (duration 18 months) of benign C/D-ELM diagnoses. The two diagnostic approaches were compared for sensitivity, predictive value and false-positive rate. Results: The series included 55 melanomas and 43 basal cell carcinomas. About 50% of malignant misdiagnosed cases were identified solely through the cancer registry. The C/D-ELM diagnosis showed a greater sensitivity for melanoma <0.76 mm thick (83 vs. 46% for clinical examination alone; ratio, 1.82) and basal cell carcinoma (79 vs. 49%; ratio, 1.62), a greater predictive value for melanoma (81 vs. 53%; ratio, 1.53) and a reduced total false-positive rate (0.3 vs. 0.9%; ratio, 0.31). Conclusion: D-ELM showed a potential to improve the clinical diagnosis of PSL.

Vitamin D and melanoma and non-melanoma skin cancer risk and prognosis: A comprehensive review and meta-analysis

Vitamin D is formed mainly in the skin upon exposure to sunlight and can as well be taken orally with food or through supplements. While sun exposure is a known risk factor for skin cancer development, vitamin D exerts anti-proliferative and pro-apoptotic effects on melanocytes and keratinocytes in vitro. To clarify the role of vitamin D in skin carcinogenesis, we performed a review of the literature and meta-analysis to evaluate the association of vitamin D serum levels and dietary intake with cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) risk and melanoma prognostic factors. Twenty papers were included for an overall 1420 CM and 2317 NMSC. The summary relative risks (SRRs) from random effects models for the association of highest versus lowest vitamin D serum levels was 1.46 (95% confidence interval (CI) 0.60-3.53) and 1.64 (95% CI 1.02-2.65) for CM and NMSC, respectively. The SRR for the highest versus lowest quintile of vitamin D intake was 0.86 (95% CI 0.63-1.13) for CM and 1.03 (95% CI 0.95-1.13) for NMSC. Data were suggestive of an inverse association between vitamin D blood levels and CM thickness at diagnosis. Further research is needed to investigate the effect of vitamin D on skin cancer risk in populations with different exposure to sunlight and dietary habits, and to evaluate whether vitamin D supplementation is effective in improving CM survival.

Dermoscopic evaluation of nodular melanoma

IMPORTANCE Nodular melanoma (NM) is a rapidly progressing potentially lethal skin tumor for which early diagnosis is critical. OBJECTIVE To determine the dermoscopy features of NM. DESIGN Eighty-three cases of NM, 134 of invasive non-NM, 115 of nodular benign melanocytic tumors, and 135 of nodular nonmelanocytic tumors were scored for dermoscopy features using modified and previously described methods. Lesions were separated into amelanotic/hypomelanotic or pigmented to assess outcomes. SETTING Predominantly hospital-based clinics from 5 continents. MAIN OUTCOME MEASURES Sensitivity, specificity, and odds ratios for features/models for the diagnosis of melanoma. RESULTS Nodular melanoma occurred more frequently as amelanotic/hypomelanotic (37.3%) than did invasive non-NM (7.5%). Pigmented NM had a more frequent (compared with invasive non-NM; in descending order of odds ratio) symmetrical pigmentation pattern (5.8% vs 0.8%), large-diameter vessels, areas of homogeneous blue pigmentation, symmetrical shape, predominant peripheral vessels, blue-white veil, pink color, black color, and milky red/pink areas. Pigmented NM less frequently displayed an atypical broadened network, pigment network or pseudonetwork, multiple blue-gray dots, scarlike depigmentation, irregularly distributed and sized brown dots and globules, tan color, irregularly shaped depigmentation, and irregularly distributed and sized dots and globules of any color. The most important positive correlating features of pigmented NM vs nodular nonmelanoma were peripheral black dots/globules, multiple brown dots, irregular black dots/globules, blue-white veil, homogeneous blue pigmentation, 5 to 6 colors, and black color. A model to classify a lesion as melanocytic gave a high sensitivity (>98.0%) for both nodular pigmented and nonnodular pigmented melanoma but a lower sensitivity for amelanotic/hypomelanotic NM (84%). A method for diagnosing amelanotic/hypomelanotic malignant lesions (including basal cell carcinoma) gave a 93% sensitivity and 70% specificity for NM. CONCLUSIONS AND RELEVANCE When a progressively growing, symmetrically patterned melanocytic nodule is identified, NM needs to be excluded.

Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy

BackgroundSeveral genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease.MethodsA large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16CDKN2A, BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16CDKN2Agenes.ResultsFor melanoma susceptibility, investigations at germline level indicated that p16CDKN2Awas exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16CDKN2Agene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16CDKN2Asilencing).ConclusionOur findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis.