A review of nevus-associated melanoma: What is the evidence?

Cutaneous melanoma may have an adjacent nevus remnant on histological examination in 30% of cases (nevus-associated melanoma, NAM), while it may appear de novo, without a precursor lesion, in the remaining 70% of cases. Nevus-associated melanoma and the concept of acquired melanocytic nevi serving as precursors of melanoma has long been considered as a controversial topic. This controversy is, in part, due to their overall low rate of transformation to melanoma and scarce data on the natural history of progression. Another matter of debate regarded the possibility that the reported differences in NAM vs. de novo melanoma were due to an underestimation of NAM in thicker lesions due to obliteration of the nevus component by the tumour. During the last few years, several evidence has accumulated in order to address these controversies. In this review, we present a comprehensive synthesis of the epidemiological, clinical, dermoscopic and genetic findings in NAM, including thin NAM, compared to de novo melanoma. Answering the questions on nevus-associated melanoma may provide further insight into the classification of these tumours and disentangle their biology and route of development from that of de novo melanoma.

Not all melanomas are created equal: a review and call for more research into nodular melanoma.

Among the histogenic subtypes of melanoma, nodular melanoma (NM) is the major contributor for thicker and fatal melanomas and it has been associated with melanoma-specific death in thin tumours, highlighting an important subgroup of 'aggressive thin' melanomas. This review provides a synthesis of the distinct characteristics of NM, with respect to epidemiology and risk factors, clinical presentation, histopathology, molecular and dermoscopic aspects, and screening practices. The real challenges are to find better biomarkers of aggressiveness and to know whether the control of such aggressive melanomas can be influenced by targeted interventions such as early detection, drug interventions and preventive strategies.

A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

BACKGROUND: Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. OBJECTIVES: To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. METHODS: We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. RESULTS: In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. CONCLUSIONS: Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Dermatoscopic features of thin (≤2 mm Breslow thickness) vs. thick (>2 mm Breslow thickness) nodular melanoma and predictors of nodular melanoma versus nodular non-melanoma tumours: a multicentric collaborative study by the International Dermoscopy Society.

BACKGROUND: Thin nodular melanoma (NM) often lacks conspicuous melanoma-specific dermatoscopic criteria and escapes clinical detection until it progresses to a thicker and more advanced tumour. OBJECTIVE: To investigate the dermatoscopic morphology of thin (≤2 mm Breslow thickness) vs. thick (>2 mm) NM and to identify dermatoscopic predictors of its differential diagnosis from other nodular tumours. METHODS: Retrospective, morphological case-control study, conducted on behalf of the International Dermoscopy Society. Dermatoscopic images of NM and other nodular tumours from 19 skin cancer centres worldwide were collected and analysed. RESULTS: Overall, 254 tumours were collected (69 NM of Breslow thickness ≤2 mm, 96 NM >2 mm and 89 non-melanoma nodular lesions). Light brown coloration (50.7%) and irregular brown dots/globules (42.0%) were most frequently observed in ≤2 mm NMs. Multivariate analysis revealed that dotted vessels (3.4-fold), white shiny streaks (2.9-fold) and irregular blue structureless area (2.4-fold) were predictors for thinner NM compared to non-melanoma nodular tumours. Overall, irregular blue structureless area (3.4-fold), dotted vessels (4.6-fold) and serpentine vessels (1.9-fold) were predictors of all NM compared to non-melanoma nodular lesions. LIMITATIONS: Absence of a centralized, consensus pathology review and cases selected form tertiary centres maybe not reflecting the broader community. CONCLUSIONS: Our study sheds light into the dermatoscopic morphology of thin NM in comparison to thicker NM and could provide useful clues for its differential diagnosis from other non-melanoma nodular tumours.

Interval cancers after skin cancer screening: incidence, tumour characteristics and risk factors for cutaneous melanoma.

BACKGROUND: The rate of interval cancers is an established indicator for the performance of a cancer-screening programme. METHODS: We examined the incidence, tumour characteristics and risk factors of melanoma interval cancers that occurred in participants of the SCREEN project, which was carried out 2003/2004 in Schleswig-Holstein, Germany. Data from 350 306 SCREEN participants, who had been screened negative for melanoma, were linked to data of the state cancer registry. Melanoma interval cancers were defined as melanomas diagnosed within 4-24 months after SCREEN examination. Results were compared with melanomas of the pre-SCREEN era (1999-2002), extracted from the cancer registry. RESULTS: The overall relative incidence of melanoma interval cancers in terms of observed/expected ratio was 0.93 (95% CI: 0.82-1.05; in situ: 1.61 (1.32-1.95), invasive: 0.71 (0.60-0.84)). Compared with melanomas of the pre-SCREEN era, the interval melanomas were thinner and had a slightly greater proportion of lentigo maligna melanomas whereas nodular melanomas were less frequent. INTERPRETATION: The results indicate a moderate performance of the SCREEN intervention with an excess of in situ melanomas. In part, the findings might be due to specifics of the SCREEN project, in particular a short-term follow-up of patients at high risk for melanoma.

The impact of dermoscopy on melanoma detection in the practice of dermatologists in Europe: results of a pan-European survey.

BACKGROUND: Dermoscopy is a widely used technique that can increase the sensitivity and specificity of melanoma detection. Information is lacking on the impact of dermoscopy use on the detection of melanoma in the real-life practice of European dermatologists. OBJECTIVE: To identify factors that influence the benefit of using dermoscopy for increasing melanoma detection and lowering the number of unnecessary biopsies in the practice of European dermatologists. METHODS: We conducted a survey of dermatologists registered in 32 European countries regarding the following: the demographic and practice characteristics, dermoscopy training and use, opinions on dermoscopy and the self-estimated impact of dermoscopy use on the number of melanomas detected and the number of unnecessary biopsies performed in practice. RESULTS: Valid answers were collected for 7480 respondents, of which 6602 reported using dermoscopy. Eighty-six per cent of dermoscopy users reported that dermoscopy increased the numbers of melanomas they detected, and 70% reported that dermoscopy decreased the number of unnecessary biopsies of benign lesions they performed. The dermatologists reporting these benefits were more likely to have received dermoscopy training during residency, to use dermoscopy frequently and intensively, and to use digital dermoscopy systems and pattern analysis compared to dermatologists who did not perceive any benefit of dermoscopy for the melanoma recognition in their practice. CONCLUSIONS: Improving dermoscopy training, especially during residency and increasing access to digital dermoscopy equipment are important paths to enhance the benefit of dermoscopy for melanoma detection in the practice of European dermatologists.

Factors driving the use of dermoscopy in Europe: a pan-European survey.

BACKGROUND: When used correctly, dermoscopy is an essential tool for helping clinicians in the diagnosis of skin diseases and the early detection of skin cancers. Despite its proven benefits, there is a lack of data about how European dermatologists use dermoscopy in everyday practice. OBJECTIVES: To identify the motivations, obstacles and modifiable factors influencing the use of dermoscopy in daily dermatology practice across Europe. METHODS: All registered dermatologists in 32 European countries were invited to complete an online survey of 20 questions regarding demographic and practice characteristics, dermoscopy training and self-confidence in dermoscopic skills, patterns of dermoscopy use, reasons for not using dermoscopy and attitudes relating to dermoscopy utility. RESULTS: We collected 7480 valid answers, of which 89% reported use of dermoscopy. The main reasons for not using dermoscopy were lack of equipment (58% of nonusers) and lack of training (42%). Dermoscopy training during residency was reported by 41% of dermoscopy users and by 12% of nonusers (P < 0·001). Dermatologists working in public hospitals were the least likely to use dermoscopy. High use of dermoscopy across the spectrum of skin diseases was reported by 62% of dermoscopy users and was associated with dermoscopy training during residency, the use of polarized light and digital dermoscopy devices, longer dermoscopy practice, younger age and female gender. CONCLUSIONS: Expanding access to dermoscopy equipment, especially in public healthcare facilities and establishing dermoscopy training during dermatology residency would further enhance the substantially high dermoscopy use across European countries.

Cross-sectional analysis of the dermoscopic patterns and structures of melanocytic naevi on the back and legs of adolescents.

BACKGROUND: Junctional (flat) naevi predominate on the extremities, whereas dermal (raised) naevi are found primarily on the head, neck and trunk. Few studies have investigated the anatomical site prevalence of melanocytic naevi categorized using dermoscopy. OBJECTIVES: To identify the prevalence of dermoscopic patterns and structures of naevi from the back and legs of adolescents. METHODS: Dermoscopic images of acquired melanocytic naevi were obtained from the back and legs of students from a population-based cohort in Framingham, Massachusetts. Naevi were classified into reticular, globular, homogeneous or complex dermoscopic patterns. Multinomial logistic regression modelling assessed the associations between dermoscopic pattern and anatomical location. RESULTS: In total 509 participants (mean age 14 years) contributed 2320 back naevi and 637 leg naevi. Compared with homogeneous naevi, globular and complex naevi were more commonly observed on the back than the legs [odds ratio (OR) 29·39, 95% confidence interval (CI) 9·53-90·65, P < 0·001 and OR 6·8, 95% CI 2·7-17·14, P < 0·001, respectively], whereas reticular lesions were less likely to be observed on the back than on the legs (OR 0·67, 95% CI 0·54-0·84, P = 0·001). Naevi containing any globules were more prevalent on the back than on the legs (25% vs. 3·6%, P < 0·001). Naevi containing any network were more prevalent on the legs than on the back (56% vs. 40·6%, P < 0·001). CONCLUSIONS: These findings add to a robust body of literature suggesting that dermoscopically defined globular and reticular naevi represent biologically distinct naevus subsets that differ in histopathological growth pattern, age- and anatomical-site-related prevalence, molecular phenotype and aetiological pathways.

Melanoma prognosis in Europe: far from equal.

BACKGROUND: Comprehensive, population-based analysis of melanoma survival throughout Europe is hindered by the uneven coverage and quality of European cancer registries, and by logistical and financial shortcomings. Mortality-to-incidence ratios (MIRs) have been used as a proxy for estimating survival for multiple cancers and to model melanoma prognosis, higher MIR values reflecting poorer prognosis. Updated and improved pan-European estimates of mortality and incidence rates for melanoma have become available through the International Agency for Research of Cancer project Globocan 2008, showing marked differences among European countries. OBJECTIVES: To analyse MIRs for melanoma across Europe and their relationship with national health expenditures, aiming to identify countries and regions with disproportionately poor prognosis. METHODS: Estimated age-standardized rates of melanoma incidence and mortality provided by Globocan 2008 were used to calculate the MIR for each European country and region. Total health expenditures per capita in European countries for 2008 were provided by the World Health Organization/Global Health Observatory. The potential correlation between MIR and total health expenditure per capita was analysed through Pearson's correlation. RESULTS: Mortality-to-incidence ratios for melanoma ranged between 0·09 in Switzerland and 0·44 in Latvia. The regional average MIR was the highest in Central and Eastern Europe at 0·35; the lowest was in Western Europe, at 0·13. We found a strong inverse correlation between the individual nation's total health expenditure per capita and the calculated melanoma MIR (r = -0·76, P < 0·05). CONCLUSIONS: While further improvement of melanoma registration is necessary, our findings reveal sharp disparities in the prognosis of melanoma across the Continent, correlated with significant differences in health care expenditures.

Demographic, behavioural and physician-related determinants of early melanoma detection in a low-incidence population.

BACKGROUND: Knowledge of the factors that influence early detection of melanoma is important in developing strategies to reduce associated mortality. OBJECTIVES: To identify sociodemographic, behavioural and medical care-related factors associated with melanoma thickness in a low-incidence population but with a high case fatality. PATIENTS AND METHODS: In a multicentre, retrospective, survey-based study of 202 patients with a recent diagnosis of invasive melanoma (< 1 year), we collected data on demographic and behavioural factors, attitudes towards prevention, access to medical care, frequency of skin self-examination (SSE) and physician skin examination (PSE) in relation to melanoma thickness. RESULTS: Thinner tumours (≤ 1 mm, 80 melanomas) were associated with female sex (P ≤ 0.049), nonnodular (superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma) histological subtypes (P < 0.001), absence of ulceration (P ≤ 0.001), and location other than lower extremity or trunk location (P ≤ 0.004). Patients married at the time of diagnosis or who performed SSE during the year prior to diagnosis were more likely to have thinner tumours than those who did not [odds ratio (OR) 3.45, 95% confidence interval (CI) 1.48-8.04 and OR 2.43, 95% CI 1.10-5.34, respectively]. Full-body skin examination by a physician was not significantly associated with thinner melanoma (OR 1.99, 95% CI 0.66-6.07). CONCLUSIONS: SSE was shown to be an important factor in the detection of thin melanoma, in contrast to partial or full-body PSE, which did not show any statistically significant effect on tumour thickness.

Skin cancer screening participation and impact on melanoma incidence in Germany--an observational study on incidence trends in regions with and without population-based screening.

BACKGROUND: The SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project involved population-wide skin cancer screening with whole-body examination by general physicians and dermatologists. It was conducted in the German state of Schleswig-Holstein (July 2003-June 2004), but not in the German state of Saarland. METHODS: The population-based registries of Schleswig-Holstein and Saarland provided data on melanoma incidence before, during, and after SCREEN to assess the association of skin cancer screening with incidence. RESULTS: Approximately 19% of the Schleswig-Holstein population participated in SCREEN (women: 27%, men: 10%). A total of 52% of all melanomas diagnosed during SCREEN in Schleswig-Holstein were detected as part of the project. Melanoma incidence increased during SCREEN (invasive melanoma in women: +8.9 per 100,000 (95% confidence intervals (CI): 6.1; 11.7); men: +4.0 per 100,000 (95% CI: 1.6; 6.4)) and decreased afterwards (women: -10.6 per 100,000 (95% CI: -13.3; -7.9); men: -4.1 per 100,000 (95% CI: -6.5; -1.7)). Similar changes were not observed in Saarland that had no such project. The differences between the two states were greatest among women, the group with the greater SCREEN participation. CONCLUSION: The SCREEN project had a substantial impact on melanoma incidence. This is consistent with the impact of effective screening for other cancers.

Melanoma incidence and mortality in Europe: new estimates, persistent disparities.

BACKGROUND: Melanoma incidence and mortality in Europe are high but there are significant gaps in the epidemiological information available across the continent. OBJECTIVES: With the aim of enhancing the planning of educational programmes for reducing the melanoma burden in Europe, we analysed the most recent incidence and mortality data for Europe with a new focus on the regional disparities of melanoma reporting. METHODS: GLOBOCAN 2008, the standard set of worldwide estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer for 2008, was used to provide the estimated age-standardized rates (world standard population) of melanoma incidence and mortality in European countries and regions. RESULTS: The estimated age-standardized incidence of melanoma (measured per 100 000 person-years) varies widely from 19·2 in Switzerland to 2·2 in Greece. The incidence rate of 4·3 of Central and Eastern Europe (CEE) is less than half of that of Western Europe. Melanoma mortality rates of 1·5 are similar in CEE and Western Europe, although rates vary with a high of 3·2 in Norway and a low of 0·9 in Greece. Over 20 000 deaths from melanoma were estimated in Europe in 2008, with CEE having the largest share (35·5%) among the four geographical European regions. Population-based data are lacking for significant parts of CEE, which must rely on estimates. CONCLUSIONS: The most recent estimates of melanoma incidence and mortality in Europe reveal sharp differences between European countries, possibly related to missed opportunities for early diagnosis and incomplete reporting of melanoma in Eastern Europe.

A defective HSV-1 vector expresses Escherichia coli beta-galactosidase in cultured peripheral neurons.

A defective herpes simplex virus 1 (HSV-1) vector, pHSVlac, has been developed that contains a transcription unit that places the Escherichia coli lacZ gene under the control of the HSV-1 immediate early 4/5 promoter. The vector pHSVlac was propagated with the HSV-1 temperature-sensitive mutant ts K as helper virus. Infection of neurons from rat superior cervical ganglia and dorsal root ganglia in primary culture resulted in stable expression of high levels of beta-galactosidase without cell death. These HSV-1 vectors should be useful for introducing genes into postmitotic cells, such as neurons, in vitro and in vivo.

Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase.

One therapeutic approach to treating Parkinson's disease is to convert endogenous striatal cells into levo-3,4-dihydroxyphenylalanine (L-dopa)-producing cells. A defective herpes simplex virus type 1 vector expressing human tyrosine hydroxylase was delivered into the partially denervated striatum of 6-hydroxydopamine-lesioned rats, used as a model of Parkinson's disease. Efficient behavioral and biochemical recovery was maintained for 1 year after gene transfer. Biochemical recovery included increases in both striatal tyrosine hydroxylase enzyme activity and in extracellular dopamine concentrations. Persistence of human tyrosine hydroxylase was revealed by expression of RNA and immunoreactivity.

Readability, content, quality and accuracy assessment of internet-based patient education materials relating to labor analgesia.

BACKGROUND: With over 90% of parturients searching the internet for health information, the quality of information is important. Web-based patient education materials (PEMs) related to labor analgesia are frequently of low readability. This study compares the readability, content, quality and accuracy of labor analgesia-related PEMs from relevant healthcare society websites and the top internet search results. METHODS: The first ten PEMs from Google searches for "labor epidural" and "labor pain relief" were compared with PEMs from North American and United Kingdom anesthesiology, obstetric and medical society websites. Readability was assessed utilizing five validated readability indices. Quality was assessed using Patient Education Materials Assessment Tool for Print (PEMAT). The PEMs were graded for accuracy by four obstetric anesthesiologists. Readability, quality and accuracy scores were compared using the independent t-test and content using Chi-square analysis. RESULTS: Society PEMs were significantly more readable than non-society PEMs for three of five readability indices, though the mean of both groups was at or above an eighth-grade (average age 13-14 years-old) reading level. The PEMAT understandability and accuracy scores were significantly higher for society websites. The most frequently mentioned topics were benefits, effects of epidural analgesia on labor and delivery, definitions, post-dural puncture headache and alternative analgesics. CONCLUSIONS: Google search results for labor analgesia lead to PEMs of variable quality and readability. For readers to be better informed, web-based PEMs should be improved or women directed to society PEMs. Inaccurate information may lead to incorrect expectations and conflict during labor, with potentially lower maternal satisfaction.

Herpesviruses: expression of genes in postmitotic brain cells.

Gene transfer into neural cells in the adult mammalian brain using vectors derived from the herpes simplex virus HSV-1 has great promise both for elucidating neuronal physiology and brain mechanisms, and for gene therapy of neurological diseases. Two kinds of HSV-1 vectors are being explored: first, defective HSV-1 vectors are small plasmids containing essential HSV-1 cis-acting functions that use HSV-1 mutants as helper virus for packaging; and second, vectors that contain a recombinant gene inserted into the HSV-1 genome. Recently, several genes that alter neuronal physiology have been expressed from defective HSV-1 vectors, both in cultured neurons and in vivo.