the incidence of cutaneous melanoma ( cm ) is rapidly increasing in europe , especially in the caucasian population .
incidences are known to vary amongst white populations , reaching 15 cases per 100,000 inhabitants per year in scandinavia and 57 cases per 100,000 inhabitants per year in mediterranean countries [ 24 ] .
fortunately , these data are matched by active research directed toward a greater identification of risk factors linked with the onset of melanoma . in this regard ,
the presence of naevi assumes particular importance as an independent and very high risk factor for the development of melanoma .
clinically dysplastic naevi and an excess number of melanocytic naevi are among the most serious known risk factors for cutaneous melanoma . in the last decade , a plethora of investigations aimed at identifying risk factors for the development of melanoma have been conducted . more recently , working on 200 patients affected by melanoma and 200 healthy control patients , nikolaou et al . confirmed that the presence of atypical naevi is an important risk factor for the development of cm , tripling the odds ratio ( or ) .
according to carli et al . , the greatest difference between subjects with or without atypical naevi is related to their number of common naevi : the authors demonstrated that more than 30 naevi are encountered in 41.5% of melanoma cases , but in only 9% of healthy control subjects ( or 8.0 ; confidence interval ( ci ) 6.310.3 ) .
even if atypical clinical features of naevi constitute a very high risk factor for cm , their partial correspondence with histologic dysplasia   indicates that the total number of naevi remains the most important factor in the development of cm .
these data confirm the major risk of dysplasia or the development of cm when the total number of naevi exceeds 100 , and the presence of an elevated number of naevi needs to be carefully evaluated in the panorama of risk factors for the development of melanoma [ 13 , 14 ] .   as a result ,
numerous studies have been undertaken in order to establish a classification of naevi and to define their physiological and pathological evolution , the majority of which have aimed to correlate the macroscopic appearance of these structures with their histopathological characteristics [ 15 , 16 ] , dividing them into dermal , composed , and junctional .  
kincannon and boutzale further divided acquired naevi into five categories according to their rough macroscopic appearance and their relationship to the skin surface , noticing that the papillomatous variant is most commonly associated with such phenotypes as blue or green eye colour and fair , light brown , or red hair .
these authors underlined the importance of any possible correlations between naevi and phenotype characters and also drew up a more accurate and detailed classification of naevi , even though it was restricted almost exclusively to dermal naevi .  
gallagher and kwan showed that naevi have a preferred body distribution in the two genders which is already evident in the pediatric age : in males naevi are more numerous on the head , neck , and trunk , whereas females show a greater distribution on their limbs .
naevi are much more numerous in children intermittently exposed to the sun , highlighting the importance of sun exposure during childhood in the genesis of benign acquired naevi .
however , the same distribution pattern in photoprotected locations raises the possibility that hormonal differences play a consistent role in the development of melanocytic naevi [ 19 , 20 ]
. the most famous and widely accepted classification of acquired melanocytic naevi was published by ackermann and magana - garcia who classify naevi into four types , of which clark naevi constitute the predominant type among commonly acquired melanocytic naevi .
when their diameter exceeds 5  mm and at least two other signs of clinical activity are present , such as irregular or poorly defined edges , uneven colouring , or erythematous patch variations in skin pattern , they are defined as atypical , whereas when histology shows the presence of specific architectural features they are diagnosed as dysplastic naevi . however , although ackerman 's classification continues to be a reference , all pigmented melanocytic naevi are grouped under the single denomination of clark naevi which does not enable the analytical investigation of naevi in the field of melanoma prevention : further steps in this direction have only led to the conviction that the presence of a small number of clark naevi has weak meaning in young patients with no melanoma familiarity . on the other hand , when clark naevi arise in older subjects , between the ages of 40 and 50 with no familiarity ,
their meaning is less clear but it is considered as an anomaly of the normal formation and growth process of melanocytes .  
several variants , whose denominations can be found in the literature , are mentioned and defined by means of clinical criteria in saurat 's book .
this publication includes the most common naevi present in the population ; sutton or halo naevus is also mentioned and congenital pigmented naevi are divided into small ( < 1.5  cm ) , medium ( 1.520  cm ) , and large ( > 20  cm ) .
further progress in this direction can be achieved by making a precise systematic table of the various subspecies of naevus , free of any excess or overlapping .
we have conducted this case - control study with the aim of observing different numbers of moles and different mole typology associations between patients affected by melanoma and control volunteers .
the analysis of naevus variants is not only of commercial value but can be of considerable practical value in the self - analysis of naevi , which is of great importance in the prevention of cm .
this analysis   makes it easier for patient and physician to know the number and distribution of the naevi , thus enabling the timely observation of any anomalous cellular activity in progress , of any lesions at risk or of a still undetected early clinical melanoma .
in addition , this study may provide a further contribution to the determination of a naevic map in the patient undergoing a routine dermatological checkup without suspect lesions , evaluating the possibility of identifying one or more categories of naevus variants for every individual in order to identify further guide lines for the study of melanoma risk factors .  
naevus variants can improve the interaction between doctors and their patients , who will be able to furnish more accurate information on the naevi and their evolution , thus providing doctors with better  guidelines  for diagnosis and therapy . in this way
, they will be able to better orient themselves in the identification of risk naevus / naevi , examining mole variant associations and their numerosity , according to the total number of naevi and the phenotypic features of the people concerned .
one of the aims our study is to try to identify the phenotypic features of individual naevus variants with a view to establishing different risk patterns for mc , which may in turn suggest different follow - up procedures .
64 cases and 183 controls were selected amongst patients at the dermatology department of federico ii university , naples between october 2009 and february 2011 .
the cases and the controls ( 102 males and 145 females ) had an average age of 34.8 years ( minimum 2 and maximum 82 ) .
the 64 cases were equally distributed between the two sexes ; of the 183 controls 70 were males and 113 females .
the cases enrolled were patients affected with nodular or superficial melanoma , the thickness of the lesion had been determined in each case ( staging model ajcc 1988 ) , and the time elapsed from the excision was calculated as between 0 and 10 years .
patients with melanoma that had developed on a malignant freckle were excluded , as these melanomas rarely break out in association with a preexisting naevus .
the controls were first - degree relatives of cases living in the same household for the same period .
all patients were caucasian and homogeneous in respect of socioeconomic indicators and occupation ( table 2 ) . before the naevus count , a trained interviewer compiled a form for each case and control .
the interview lasted about 15 minutes and included the following data : residence , phenotype characteristics such as eye colour ( brown , hazel , green , and blue ) , hair colour ( black , brown , fair , and red ) ; phototypes for groups and subgroups from i to iv , ( since v and vi are practically absent in our area for ethnic reasons ) , melanoma familiarity , sunburn history subdivided by age ( juvenile 015 years old , and adult over 15 years old ) , and use of sun beds .
the naevi were evaluated after being classified into one of three major groups : the common acquired melanocytic naevi ( nmac ) ( > 2  mm ) , congenital naevi , and atypical naevi .
the location of each one was reported : head or neck , arm , upper arm , hands , chest , abdomen , upper back , lower back , thigh , and feet .
sun freckles or ephelides were recorded by a number code ( l  =  none , 2  =  from 1 to 5 , and 3  =  more than 5 ) .   those naevi which were identifiable as atypical
were reported separately from the total count . in order to minimise possible errors in the naevus count and according to data reported in the literature , a series of clinical criteria identifying the variants was established ( table 1 ) , based on clinical morphological criteria , that considered the following : relationship to the skin surface , this was used by the dermatologists to identify every naevus lesion . for each variant ,
the presence of naevic elements and their number was reported , as well as the total number of variants present and the total number of naevi > 2  mm , regardless of their variant group membership .
univariate analysis was carried out , followed by a chi - square test to evaluate the degree of association between several variables . finally ,
the or and the 95% confidence limit were adjusted for age , gender , number of naevi , and some known risk factors for cm , such as phototype i - ii , melanoma familiarity , and past sunburn history .
more than 70% of the sample had homogeneous phenotypes : phototype ii or iii ; dark hair ; dark eyes ( 9% of the subjects phototype i , 40% phototype ii ; 35% phototype iii ; 14% phototype iv ) .
the sample was also homogeneous in relation to the total number of naevi : 42% of cases and 45% of controls , thus nearly half the sample reported a total number of naevi ranging between 10 and 50 elements .  
67% of cases and 80% of controls were negative for childhood sunburn : more than 75% of the sample did not present a childhood sunburn risk factor . with regard to our first aim
, that is , the distribution of the single types in the sample , our study showed that the small brown naevus was present in more than 70% of controls and of cases . the raised brown naevus , on the other hand , was found in 93% of control subjects and in only 7% of cases .
the target naevus was identified in 7.8% of the cases and in 16.1% of the controls .
the association small brown + small black is equally distributed between the two groups : 27% of the cases and the controls .
the presence of the target naevus varies in the two groups when it is the only type present and , when in association with others , more predominantly in cases ( target : 16% of cases and 8% of controls ; target  +  small brown : 16% of cases and 7% of controls ; target  +  small brown  +  small black : 10% of cases and 3% of controls ; target + small brown + small black + large brown : 8% of cases and 2% of controls ) .
the presence of the small brown does not seem to be associated with cm ( small brown or 2.05 ; ci 1.04.42 ) .
the risk increases when there is also the target variant ( target or 3.65 ; ci 1.49.7 ) .
the raised brown naevus , on the other hand can be considered as protective for the development of cm ( raised nevus or 0.2 ; ci 0.030.8 ) .
it can be seen that among subjects with an equal number of naevi , a greater number of variants corresponds to a greater cutaneous melanoma risk .
the results were relative to the variants indicated in table 3 . with an equal number of naevi
, the combination of only two variants was found to be of slight significance : ( small black + large brown or 3.5 ; ci 1.39.2 ) ; ( target + large brown or 3.6 ; ci 1.111.2 ) ; ( small black + large brown + large black or 5.5 ; ci 1.421.7 ) ; ( target + small brown + small black or 5.9 ; ci 1.523.2 ) indicating that apart from the number of naevi , naevus variants might influence the degree of risk . on the other hand the or does not change when the small brown variant is added to the association of small black and small brown ( small brown + large brown + small black ( or 3.5 ; ic 1.39.5 ) , small black + large brown ( or 3.5 ; ic 1.39.2 ) ) .
analysing these data , it can be seen that a further significant element is provided by the specific impact of the different variants : the data indicate that the presence of the very common small brown naevus , does not modify the or , whereas the target naevus requires more careful evaluation ( or 3.65 ; ci 1.49.7 ) .
moreover , the association of the target naevus with other variants , increases the degree of risk [ target + small brown or 5.25 ; ci 1.815.4 ] ; [ target + small brown + small black or 5.9 ; ic 1.523.2 ] ; [ target + small brown + small black + large brown or 5.0 ; ic 1.122.4 ] .
our study indicates that some variants and/or variant combinations , do not significantly increase risk .
( fried egg or 0.4 ; ci 0.081.86 ; p = 0.23 ) ; ( unna or 0.94 ; ci 0.461.90 ; p = 0.8 ) ; ( meischer or 1.26 ; ci 0.52.9 ; p = 0.6 ) .
the self - assessment of pigmented lesions remains an important step in the prevention of skin melanoma . in an australian study , carried out to determine the correspondence between the patient 's and the dermatologist 's naevus check
, it was shown that the number of pigmented lesions is always underestimated by the patient , but agreement increases for atypical melanocytic naevi ; however , the role of the atypical naevus has been the subject of much debate in the literature and elsewhere , and , of course , it is not so easy to diagnose clinically .
our study aims to introduce the differentiation of naevus variants among the monitoring criteria of risk factors for cutaneous melanoma .
the results show that even if the total number of naevi represents a risk factor for the development of cutaneous melanoma , orientation in the naevus panorama of a specific subject requires the identification of several naevus variants .
the most common naevus variants , such as dermal naevi and homogeneously pigmented naevi ( small and large brown or small and large black naevi ) can not alone represent a risk marker ; however the combination of two or more variants becomes a significant risk marker , and their combination in a person thus enables the identification of groups of subjects as reference targets potentially at risk of developing cutaneous melanoma . on the other hand
, people presenting the target naevus in association with other naevus variants , have a major rearrangement and activity of pigmented lesions , and therefore require a more rigorous follow - up procedure
. the greater variability of this variant is perhaps also expressed through its greater clinical inhomogeneity .
this introduces a further aspect of our results : it is important to consider carefully not only the non - uniformity of a single type but also the general non - uniformity of the whole naevus panorama .
the data actually available in the literature indicate that when the total number of naevi present in a subject increases , the risk of developing cutaneous melanoma also increases .
a further datum emerges from our study : when two subjects present a similar number of naevi , the greater risk for cutaneous melanoma is linked to the greater number of naevus variants .
subjects having a moderate number of lesions but presenting clinical inhomogeneous pigmentation are included in the group of subjects at risk .
conversely , subjects with an elevated number of naevi but with a homogeneous panorama and low variability , can be observed with greater tranquillity , without however neglecting other risk factors .
the classification of naevus in variants can be an indicator of clinical predictivity particularly in subjects who present naevi and especially an elevated number of naevi .
furthermore , some variants considered singularly can play a key role in determining the clinical picture of the subject and are to be evaluated with great attention .
consider , for example , naevi such as the small brown naevus whose presence or absence appears to be totally uninfluential , whereas the presence of others , such as the bullseye naevus , can greatly modify the dermatologist 's attitude toward the patient .
 
 background . 
 the incidence of cutaneous melanoma is rapidly increasing in europe . 
 active research is directed toward the identification of naevi as a risk factor . objective . 
 the aim of our case - control study was to observe different numbers of moles and different mole typology associations in order to evaluate clinical predictivity and to establish a new classification for some naevus variants . 
 methods . 
 a case - control study was carried out , enrolling 64 cases affected by melanoma and 183 controls , between october 2009 and february 2011 . 
 each patient was interviewed and subjected to clinical examination . 
 the resulting data were analysed using the statistical elaboration program spss 16.0 . 
 results . 
 the association of target naevus with other variants increases the degree of risk ( target + small brown odds ratio 5.25 ; confidence interval 1.815.4 ) ; ( target + small brown + small black + large brown odds ratio 5.0 ; confidence interval 1.122.4 ) . 
 therefore , other variants and/or other variant combinations do not significantly increase risk . conclusion . 
 people presenting two naevus variants in association with other naevus variants seem to run a major risk . 
 the general nonuniformity of the whole naevus panorama should be carefully considered . 
1. Introductions
2. Aims
3. Material and Methods
4. Results
5. Conclusion