Total Naevus Count Research Articles

Genome-Wide Association Study Suggests the Variant rs7551288*A within the DHCR24 Gene Is Associated with Poor Overall Survival in Melanoma Patients.

Simple SummaryThe aim of this work was to investigate prognostic genetic factors in melanoma patients. Phenotypic and disease data as well as biomaterial were collected after informed consent from patients followed up in a Skin Cancer Center of a University clinic. Genome-wide analysis (GWAS) was performed with survival data of 556 melanoma patients and genetic data including more than 300,000 common polymorphisms. The SNP rs7551288 reached suggestive genome-wide significance (p = 2 × 10−6). This intronic variant of the DHCR24 gene is involved in the cholesterol synthesis pathway. Further analyses and a literature review suggest an important role of this locus for the clinical course of disease in melanoma patients.Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected (p = 2 × 10−6). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.

Natural history of naevi: a two-wave study.

Naevi number changes with age. Thus, a better understanding of naevus biology will shed more light on the genetic and environmental factors involved in melanoma development. To use a two-wave study to better understand the evolution of naevi in healthy adults. This study is a prospective two-wave study based on adult twins from the TwinsUK registry (n = 414) who underwent total body naevus counts with an interval of at least 15 years. A negative binomial hierarchical model with two levels, the individual and the twin pair, was used to estimate expected changes in naevus count between the first and second visit, at any specific body site and on the whole body. The model was adjusted for age, calendar year at the first visit, height and skin type. The mean age of participants was 46 years at the first visit and 63 years at the second visit (the mean elapsed time between visits was 17 years). An increase in naevus count was observed in 235 (57%) participants and a decrease was observed in 166 (40%). The mean difference in total naevus count between the two visits was nine. The expected total body naevus count increased, on a logarithmic scale, by 0·28 [95% confidence interval (CI) 0·16-0·40] with a change in the incidence rate of total body naevus count of 32% (95% CI 17-49%). However, the observed increase in naevus count over time was observed only on the upper parts of the body, whereas there was no evidence of an increase on the lower parts. Naevus counts increased slightly over time at older ages, but this was dependent on body site. The overall decrease in naevus counts previously reported in cross-sectional studies has not been confirmed by this longitudinal study.

'Inverse association between the total naevus count and melanoma thickness'.

Individuals with a high total naevus count (TNC) are at a higher risk to develop melanoma, and screening efforts have been largely focused on this group. However, some studies suggest that melanomas of patients with many nevi are thinner than those of patients with few nevi. Additionally, nodular melanoma has been associated with individuals with a low naevus count. To investigate the association between TNC and melanoma Breslow thickness. A two-centre retrospective study from 1 January 2016 to 1 January 2018. This included three hundred and twenty-six consecutive melanoma patients from two tertiary melanoma centres. The mean age at presentation was 58.3years (SD=15.9), and the majority (54.9%, N=179) were men. Incidence of new in situ and invasive melanomas and correlation with TNC were measured. The mean total naevus count for patients presenting with in situ melanoma was 57.2 (range 4-178), while for patients presenting with invasive disease was 31.5 (P=0.01). In situ disease was associated with a higher TNC across all ages. For invasive melanoma, a positive association between age and Breslow thickness was observed, while TNC was inversely associated with Breslow thickness. Each additional naevus accounted for a 4% decreased likelihood that the subject had invasive disease. Patients with a higher naevus count had thinner melanomas and more melanomas in situ, independent of age and sex.

Association of clinicopathological features of melanoma with total naevus count and a history of dysplastic naevi: a cross-sectional retrospective study within an academic centre.

High naevus count (HNC) (≥ 50 naevi) and presence of dysplastic naevi (DN) are risk factors for malignant melanoma (MM); however, MMs also occur in patients with low naevus count (LNC) (< 50 naevi) and in patients without DN. Little is known about differences between MMs in these groups. To characterize the clinicopathological differences between MMs in patients with HNC and those in patients with LNC, with or without biopsy-proven DN. This was a cross-sectional retrospective chart review of 281 patients with MM seen between April 2013 and March 2014 at an academic pigmented lesion clinic (Boston, MA, USA). Patients with LNC MMs were diagnosed at an older age (51 vs. 41 years, P < 0.001, OR = 0.95, 95% CI 0.93-0.97), with more aggressive MM features, including greater Breslow thickness (1.1 vs. 0.8 mm, P = 0.01), more mitoses (2 vs. 1 mitoses/mm2 , P < 0.001), lower rate of superficial spreading subtype (58 vs. 78%, P < 0.01, OR = 2.57, 95% CI 1.31-5.03) and higher MM stage (P < 0.001), compared to patients with HNC. Patients with DN had similar trends as those in patients with HNC described above, and in addition, were more likely to have a truncal MM (55 vs. 39%, P < 0.01, OR = 1.97, 95% CI 1.22-3.18) with less ulceration (13 vs. 29%, P < 0.01, OR = 0.36, 95% CI 0.19-0.71). Patients without DN were more likely to have a history of a non-MM skin cancer (32 vs. 19%, P = 0.01, OR = 0.49, 95% CI 0.28-0.85) and an amelanotic MM (33 vs 21%, P = 0.03, OR = 0.55, 95% CI 0.31-0.96). Patients with LNC may develop MMs with more aggressive features at an older age than patients with HNC. A history of biopsy-proven DN reveals distinct MM differences compared to patients without DN.

Lymph nodes' capsular naevi are associated with high naevus count in melanoma patients: a case-control study.

Capsular naevi (CNs) in lymph nodes (LNs) are relatively common, occurring in 3-22% of patients who undergo LN surgery for melanoma. Naevus count is one of the principal risk factors for melanoma, as well as a prognostic factor in melanoma patients. However, little is known about the occurrence of CN in melanoma patients on the basis of their naevus count. A case-control study was performed, to look at the naevus count differences between CN-positive and CN-negative melanoma patients. Cases (CN positive) were matched for age, sex and Breslow thickness with controls (CN negative). Total naevus count was recorded at diagnosis and compared between the two groups. This study was conducted in a tertiary referral academic centre for skin cancer. Twenty-two positive CN patients were matched with 22 negative CN patients. The mean Breslow thickness was 2.66 mm (range: 0.6-9). Positive CN patients were significantly associated with an increasing naevus count on their skin (P=0.02). Patients with more than 100 naevi reported an odds ratio of 7.78 on having a CN compared with patients with fewer than 50 naevi on their skin (P=0.02). An increased melanocytic migration to LNs might be the reason for the association between CNs and a high number of melanocitic naevi on the skin. This could shed some light on the physiology of melanocytes and could be an easy way to predict patients at greater risk of having CNs.

Prediction of high total naevus count to estimate melanoma risk. We need more, don't we?

Prediction of high total naevus count to estimate melanoma risk. We need more, don't we?

Heritability of naevus patterns in an adult twin cohort from the Brisbane Twin Registry: a cross-sectional study.

Heritability of naevi counts is widely acknowledged as a potential surveillance parameter for prevention purposes. The contribution of heritability to the changes seen in naevus number and morphology over time and their corresponding dermoscopic characteristics is unknown, but is important to understand in order to account for adequate prevention measures. To identify naevus characteristics that are strongly influenced by heritability. This cross-sectional study included 220 individuals [76 monozygotic (MZ), 144 dizygotic (DZ)], recruited from the Brisbane Twin Naevus Study. Participants received full body imaging and dermoscopy of naevi ≥ 5 mm in diameter. Dermoscopic type, total naevus count (TNC), change in TNC with age, and naevus distribution, size, colour and profile were compared between MZ and DZ twins. Heritability of these traits was assessed via Falconer's estimate. Significant differences were found in comparing MZ and DZ twins for TNC, numbers of naevi 5·0-7·9 mm in diameter, counts of light-brown naevi, naevi on the back and sun-protected sites, and naevi with the 'nonspecific' dermoscopic pattern. This study strongly supports a heritable component to TNC, as well as changes in TNC, and the number of medium-sized naevi, light-brown naevi, specific sites and certain dermoscopic features in adults. These characteristics should be taken into account by naevus surveillance programmes and further studied to identify candidate gene associations for clinical and dermoscopic patterns in conjunction with melanoma risk stratification.

Age-related prevalence and morphological appearance of facial skin tumours: a prospective, cross-sectional, observational, multicentre study with special emphasis on melanocytic tumours.

The clinical and histopathological diagnosis of skin tumours arising on the face may be challenging. An improved knowledge about the age-related patterns of facial skin tumours may aid the correct diagnosis and management. We conducted a prospective, cross-sectional morphological study to investigate the age-related frequency and morphological variability in facial skin tumours in a cohort of consecutive subjects attending two skin lesion clinics in Italy between June and September 2011. A total of 454 consecutive subjects (249 women; 55.5%) presenting with a total of 1866 facial tumours were enrolled in the study. Of the entire cohort, 54 (11.9%) subjects had no facial lesion. Total body naevus count correlated significantly with the mean number of facial lesions (ρ=0.289, P<0.001). The majority of flat lesions were pigmented (1056; 75.70%), compared to palpable (233; 17.40%) and raised lesions (93; 6.90%), the association being statistically significant (Pearson's chi square, P<0.001. Considering melanocytic tumours only, the frequency of flat lesions significantly decreased with increasing age, while the number of palpable and raised lesions increased with increasing age (chi-square, P<0.001). This trend was mainly due to naevi, whereby pigmented melanocytic naevi decreased with increasing age. Conversely, the percentage of non- pigmented naevi increased with increasing age (chi-square, P<0.001). The study was conducted in skin lesion clinics in Italy, thus any general conclusions with respect to common traits or features based on the phenotypic and genetic diversity within the European population cannot be stated. Our study suggests that a high number of facial naevi could predict a high total naevus count. Moreover, naevi present a different morphological appearance during lifetime being initially flat, small and pigmented and becoming later raised, large and hypopigmented. Instead, lentigo maligna is an intraepidermal proliferation that typically presents as flat, large pigmented macule. A given histopathological diagnosis of a junctional naevus of a flat, facial pigmented macule of an elderly should be critically reviewed and treated with caution.

Indicators for the total number of melanocytic naevi: an adjunct for screening campaigns. Observational study on 292 patients

The presence of multiple melanocytic naevi is a strong risk factor for melanoma. Use of the whole body naevus count to identify at-risk patients is impractical. To (i) identify a valid anatomical predictor of total naevus count; (ii) determine the number of naevi that most accurately predict total naevus count above 25, 50 and 100; and (iii) evaluate determinants of multiple melanocytic naevi and atypical naevi. Clinical data from 292 consecutive Spanish patients consulting for skin lesions requiring debriding were collected throughout 2009 and 2010. Correlations between site-specific and whole body naevus counts were analysed. Cut-offs to predict total naevus counts were determined using the area under the receiver operating characteristic curve. The studied population was young (median age 31 years, interquartile range 28-43). The naevus count on the right arm correlated best with the total nevus count (R(2) 0.80 for men, 0.86 for women). Presence of at least five naevi on the right arm was the strongest determinant of a total naevus count above 50 [odds ratio (OR) 34.4, 95% confidence interval (CI) 13.9-85.0] and of having at least one atypical naevus (OR 5.7, 95% CI 2.4-13.5). Cut-off values of 6, 8 and 11 naevi on the right arm best predicted total naevus count above 25, 50 and 100, respectively. Our results support the arm as a practical and reliable site to estimate the total naevus count when screening or phenotyping large populations. Threshold values for the number of naevi on the arm are proposed to help identify patients for melanoma screening.

New insights in naevogenesis: Number, distribution and dermoscopic patterns of naevi in the elderly

It is well recognized that the number and patterns of acquired melanocytic naevi vary with age, but little is known about naevus patterns in the elderly. This is a cross-sectional study assessing the prevalence, dermoscopic pattern and anatomical distribution of naevus subtypes in a stratified cohort aged between 60 and 89 years. Fifty-nine patients who attended the Queensland Institute of Dermatology were recruited randomly and evenly distributed into three age groups: 60-69 years; 70-79 years; and 80-89 years. For each participant, total naevus count and morphological naevus types were recorded with respect to age, sex and anatomical location. Flat (Clark's) naevi were further subclassified according to the dermoscopic pattern as reticular, globular or structureless. Using non-parametric methods, naevus counts in the elderly decreased due to the disappearance of reticular naevi (P < 0.05). By contrast, structureless and intradermal (Unna's and Miescher's) naevi seemed to persist even into older age. Naevi on the trunk, limbs, head and neck represented 57.6%, 31.0% and 11.3%, respectively. Notably, no reticular naevi were found on the head and neck area. There is a progressive reduction in total naevus counts with advancing age with respect to a cohort aged greater than 60 years.

Swedish CDKN2A mutation carriers do not present the atypical mole syndrome phenotype

Phenotypic characteristics were examined in melanoma-prone southern Swedish CDKN2A (p16-113insArg/p14ARF-128insSer) mutation families, in relation to the CDKN2A genotype, nevi, clinically atypical nevi (CAN) and melanoma. Individuals from eight melanoma-prone families, with index patients carrying the CDKN2A mutation, were offered skin examinations and genotyping (CDKN2A and MC1R). Ninety-three individuals above 18 years of age participated; 29 invasive melanomas in 16 patients were recorded, all in the 38 verified CDKN2A mutation carriers. Median age at diagnosis was 36 years. Several MC1R variants were observed. A significant correlation to CAN (P=0.01) and red hair colour (P=0.02) could be confirmed in melanoma patients. A positive mutation status (CDKN2A) was correlated to one or more CAN (P=0.007) but neither to blue eyes, red hair colour, heavy freckling nor high number of nevi. For mutation carriers, median total naevus count was 24 and interquartile range was 12-47 (mean 31); whereas for the whole cohort, median total naevus count was 12 and interquartile range was 5-25 (mean 22). No participant fulfilled the atypical mole syndrome phenotype criteria. Melanomas were diagnosed only in mutation carriers, and melanoma diagnosis was statistically correlated to the presence of one or more CAN and red hair colour, supporting the possible synergistic effect of a MC1R mutation on increased risk of melanoma in patients with a CDKN2A mutation. Family history, with verified tumour diagnoses, remains an important clinical tool for finding mutation carriers for referral to clinical geneticists and simultaneous presence of CAN in probable mutation carriers might strengthen this indication. The atypical mole syndrome phenotype was, however, not verified in the studied families and total naevus counts were low.

Frequency and distribution pattern of melanocytic naevi in Estonian children and the influence of atopic dermatitis

There is a strong correlation between naevus number and prospective melanoma risk. Melanoma is one of the most rapidly increasing cancers in Estonia and primary prevention programmes for melanoma that target risk behaviour in the sun have so far not been launched. The naevus profile was examined in 549/700 9-year-old Estonian children (282 boys and 267 girls) and the presence of active atopic dermatitis (AD) was registered. There was a wide range of naevi (4-121) and a median total body count of 26. There was no difference in naevus count between boys and girls. No dysplastic naevi were found. Thirty-nine of 549 children (7%) had at least one lesion clinically diagnosed as a congenital naevus. Boys had more naevi on the face (median 4) and trunk (median 12) than girls (median 3 and 9, respectively, P < 0.001). Girls had more naevi on the legs compared with boys (median 4 and 3, respectively, P < 0.01). Fifty-four out of 549 (9.8%) had naevi on the palms and 18/549 (3.3%) on the soles. Children with fair skin, freckles and light hair and eye colours had significantly more naevi than those with darker colours. Thirty-one of 549 (6%) children had AD diagnosed on the examination day and they had a lower total naevus count (median 20) compared with children with no AD (median 27, n = 518, P < 0.05). The naevus situation in Estonian children today might constitute a starting point for evaluating the efficiency of coming preventive measures as a change of naevus number in children might serve as an early marker for a change in melanoma incidence.

Prevalence and anatomical distribution of naevi in young Queensland children.

Sunlight is the principal environmental cause of melanoma and has also been implicated in the pathogenesis of melanocytic naevi. Epidemiological evidence indicates that childhood is a period during which melanocytes are susceptible to the effects of sunlight, yet little is known about the development of naevi in infancy. We conducted a survey of child-care centres to document the prevalence and anatomical distribution of melanocytic naevi among 193 young children aged 1-3 years in Brisbane, Australia (latitude 27 degrees S). Naevi were counted on all skin surfaces except for the scalp, buttocks and genitalia. Overall, almost 90% of children in the study sample had at least 1 naevus of any size, and more than 30% of children had 10 or more naevi. Total naevus counts ranged from 0 to 45 and were strongly determined by age. When taken together, naevus densities were highest on exposed body sites such as the face and limbs; however the density of large naevi (> or = 5 mm) was significantly higher on the trunk than on the face, neck and ears. These data support the concept that melanocytic neoplasia commences early in life and that naevus evolution is influenced by the anatomical site of the target cell.

Regional distribution of melanocytic naevi in relation to sun exposure, and site-specific counts predicting total number of naevi.

The role of exposure to ultraviolet light in the formation of melanocytic naevi was analysed by investigating the regional naevus distribution in 310 subjects (30-50 years) from a Swedish census file. The lateral aspect of the arms and the back had the largest concentration of naevi. The mean naevus count per unit surface area was higher in intermittently exposed than in rarely exposed skin (p less than 0.001), while the lowest mean count was found in chronically exposed skin. These results support the idea that intermittent exposure to ultraviolet light has a "naevogenic" effect while chronic exposure might be protective. Dysplastic naevi had a distribution pattern quite different from common naevi. Considering the distribution pattern solely, dysplastic naevi seem to develop independently of exposure to ultraviolet light. The numbers of naevi in different skin areas were tested for their power in predicting the total body naevus count. The strongest correlations were found between total counts and counts on the anterior surface of the thighs and the lateral aspect of the arms. Counts from any of these areas will provide a practical and satisfactory estimate of the total number of naevi.

Genetic susceptibility to naevi – a twin study

The risk of malignant melanoma to an individual is strongly related to their total number of benign melanocytic naevi. To investigate the possibility that numbers of naevi may have an inherited basis, naevi were examined in 23 monozygotic and 22 dizygotic twin pairs. A strong correlation in total numbers of naevi 3 mm or more in diameter was observed between MZ twins (intraclass correlation 0.83), but there was no significant correlation between DZ twins (correlation -0.24). There was no increased concordance in presence of naevi 5 mm or more over that expected by chance, for MZ or DZ twins. The results suggest a strong inherited basis for total naevus count and hence melanoma risk, perhaps involving a number of interacting genes.