Clinical and epidemiological aspects of subtypes of melanocytic nevi (Flat nevi, Miescher nevi, Unna nevi)
Published Web Locationhttps://doi.org/10.5070/D39bh0r2t8
Clinical and epidemiological aspects of subtypes of melanocytic nevi (Flat nevi, Miescher nevi, Unna nevi)University Hospital, Lübeck, Schleswig-Holstein, Germany. firstname.lastname@example.org
Constanze Witt, Sven Krengel MD
Dermatology Online Journal 16 (1): 1
The term "melanocytic nevus" comprises a group of clinically and pathologically distinct subtypes. In this prospective clinical study we evaluated the frequency, localization, and age and gender distribution of flat nevi (FN), Miescher nevi (MN), and Unna nevi (UN) in a caucasian population. Nevi were counted in 400 patients, of which 47 had a history of melanoma. Additionally, the patients answered to a detailed UV questionnaire. Flat nevi represented the most common type of melanocytic nevi, with a peak in the 3rd decade of life. They were mostly found on the extremities and on the trunk. Miescher nevi were most common in the 6th decade and were predominantly found in the head and neck region. Unna nevi showed a maximum in the 8th decade and they were mainly situated on the trunk. The counts of all three nevus subtypes were elevated in the melanoma group. Our results confirm that FN, MN, and UN represent melanocytic nevi with distinctive morphological and clinical characteristics. The role of sunlight seems to be more prominent in the pathogenesis of FN. The precise description of FN, MN, and UN may serve as a base for a pathogenetic distinction of subtypes of melanocytic nevi in the future.
Nevi represent benign melanocytic neoplasms that have importance as facultative precursors of and predictors of cutaneous melanoma. In daily clinical practice high nevus counts help to identify persons at risk. Although the epidemiological relations between nevi and melanoma have been studied extensively, most studies do not differentiate between subtypes of melanocytic nevi.
According to the classical conception of melanocytic nevi, junctional, compound, and dermal nevi represent different stages of a pathogenetic sequence ("Abtropfung") . However, this view has long been debated and it has been suggested that dermal nevus cells develop from melanocytic precursor cells residing in certain niches, e.g., the bulge region of hair follicles . Moreover, recent data point to the presence of scattered melanocytic cells in the dermal connective tissue of normal adult skin at low concentration . The nevi of an individual are composed of flat and raised lesions, the former showing predominantly junctional and the latter predominantly dermal melanocyte aggregates. Earlier histological studies demonstrated important age-related and body-site-dependent characteristics of these nevus subtypes [for a review, see 2]. The traditional histological terms "junctional," "compound," and "dermal" nevi are misleading because most junctional nevi show at least a few dermal melanocytic cells and, conversly, there are only few dermal nevi that completely lack melanocytic cell proliferations in the basal epidermis. On histopathological and clinical grounds, a simple concept has been suggested by Ackerman and Magana-Garcia  that categorizes nevi into flat, exophytic, and endophytic nevi. Spitz nevi form a separate category. Histologically, flat nevi ("Clark type") predominantly show nevus cells at the dermo-epidermal junction and in the papillary dermis. In exophytic nevi, ("Unna type") the melanocytic cell aggregates are arranged in the papillary dermis, whereas endophytic nevi ("Miescher type") show nevus cells extending to the deep reticular dermis; the terms "exophytic" and "endophytic" describe the histological arrangement of the melanocytic cell aggregates rather than the clinical appearance. This classification refers to the overall histological pattern ("silhouette") of melanocytic nevi and allows an easier clinical appraisal of the presumed histological picture compared to the pseudo-accurate distinction between "junctional," "compound," and "dermal" nevi. Even if these nevus patterns yet lack a pathogenetic definition, new insights into the molecular heterogeneity of nevi, e.g., BRAF- and NRAS-mutational status, will allow more precise molecular-morphological correlations in the near future.
As the above-mentioned nevus subtypes are readily identifiable by clinical examination in most cases, we conducted a nevus count study differentiating between flat nevi (FN), Unna nevi (UN), and Miescher nevi (MN). Although Ackerman and Magana-Garcia originally suggested to designate flat nevi as "Clark nevus," we avoid this term because it can easily be confused with the ill-defined term "dysplastic nevus." The study included patients of all age groups. A main goal of the study was to clarify the distribution of nevus subtypes with respect to location, age, and gender. Secondly, we addressed the question of whether or not the well-known association between total nevus counts and melanoma also applies to the different nevus subtypes. We further measured certain clinical signs of UV exposure and non-melanocytic skin lesions (senile/solar lentigines, erythrosis interfollicularis colli, solar elastosis, seborrheic keratoses). Additionally, historical data about the personal history of sun behavior were obtained from each patient with a detailled questionnaire. The questionnaire data have been analyzed separately in a published study . In the present work we will therefore only discuss these data in relation to nevus subtypes.
Materials and methods
Between February and August, 2005, we counted melanocytic nevi in 400 consecutive patients (5-88 years of age) who presented to the outpatient department of the dermatology clinic for different skin problems. The study was approved by the local ethics committee and we obtained informed consent prior to inclusion in the study. From the 400 patients, 47 had a history of melanoma, reflecting the fact that the clinic has special consultation hours for melanoma patients. After answering to a detailed questionnaire, each patient underwent a whole-body examination, with exception of the genital and gluteal region. The examination was performed by an experienced dermatologist (S.K.) or a trained, postgraduate medical student (C.W.). Control patients, who were examined by both investigators, showed an interobserver variation of <5 percent. All melanocytic nevi were counted irrespective of their size. The numbers were determined for each body region.
The majority of melanocytic nevi presented as flat or only slightly elevated light to dark brown macules and plaques. In the absence of any of the below-mentioned criteria of non-melanocytic lesions, these were designated as FN. Exophytic, nodular or plaque-like, soft nevi with a papillomatous surface (UN), and dome-shaped, firm, smooth, skin-colored to brown papular nevi (MN) were counted separately (Fig. 1). Non-melanocytic pigmented skin lesions were differentiated from melanocytic nevi by the following clinical criteria: 1) solar/senile lentigines (grey-brown macules with sharp borders, usually on the face and lower arms), 2) freckles/ephelides (numerous, mostly small, tan-brown to reddish macules with irregular borders, mostly on face and shoulders), and 3) seborrhoeic keratoses (tan or grey-brown, sharply bordered papules or plaques with horn pearls and a waxy surface). To prove the accuracy of the clinical diagnosis, we evaluated the histological outcome in 50 consecutive nevi (FN, UN, MN) that were excised for cosmetic reasons in an independent group of patients. The clinico-histological correlation in this sample was >95 percent (data not shown).
|Figure 1a||Figure 1b|
|Figure 1c||Figure 1d|
|Figure 1e||Figure 1f|
|Figure 1. Typical clinical appearance of nevus subtypes:|
1a and 1b. Flat nevi
1c and 1d. Miescher nevi
1e and 1f. Unna nevi
Correlations between nevus subtypes and different clinical and historical data (age, gender, constitutional variables, e. g., hair and eye color, signs of chronic skin damage, history of sunburns, and biographic information on outdoor habits) were statistically analyzed. Age and sex differences, as well as differences between the melanoma und non-melanoma group, were assessed with nonparametric Mann-Whitney-U-tests and Kruskal-Wallis-H-tests. The proportions of the total surface area attributed to different body sites were based on the rule of nines used for burn area calculations . Nevus densities were calculated as follows:
Differences in site-specific counts and densities of nevi were assessed by nonparametric paired Friedman tests. In addition, we used linear regression for rising or falling tendencies of characteristics, respectively, and calculated odds ratios for the risk of melanoma dependent on the number of facial nevi. Statistical analysis was performed using IBM® SPSS® Statistics software (Version 15.0).
From the 400 patients included in the study, 47 had a history of melanoma. The mean age was 52.5 years (median 56 y, standard deviation [sd]=17.98) in the non-melanoma group (n=353; 56.7% female, 43.3% male) and 58.6 years (median 63 y, sd=15.14) in the melanoma group (n=47; 55.3% female, 44.7% male). The mean age at diagnosis of melanoma was 52.5 years (sd=17.78), the mean thickness of melanoma was 2.7 mm (sd=2.94).
The mean total nevus count in all patients was 64 (median 35, sd=75.93; non-melanoma group, 56 nevi [median 32], sd=63.30; melanoma group, 125 nevi [median 80], sd=122,74; p<0.001; U test).
Stratification for age groups (decades) showed a significant peak of total nevus numbers in the third decade (21-30 years of age), followed by a gradual decline. The differences between the melanoma group and the non-melanoma group again were significant for all decades between 21 and 80 years of age.
Nevi clinically diagnosed as flat nevi (FN) represented the most common nevus subtype (91.59% of all nevi, 92.46% in the melanoma group, 91.33% in the non-melanoma group). Miescher nevi (MN), which were most commonly found in the head and neck region (45.5% of all MN, vide infra), represented 5.84 percent of all nevi (5.17% in the melanoma group, 6.05% in the non-melanoma group). Unna's nevus (UN), mainly situated on the trunk (65.5%), was the least common nevus subtype in both groups (2.37% in the melanoma group, 2.63% in the non-melanoma group). The counts of all three nevus subtypes (FN, MN, UN) were significantly higher in the melanoma group (p<0.001; U test). The numbers are given in Table 1.
When differentiated for gender and body regions, 43.9 percent of all nevi in females were found on the lower extremities (mean count 27.91, median 13, sd=39.1), whereas in males, slightly more nevi were situated on the trunk (37.9%) than on the lower extremities (33.52%; p<0.001 for differences between body-sites in each gender; Friedman test). FN were most common on the lower extremities in females (47.2% of all FN, mean count n27.6, median 13, sd=39.1); in males, FN were nearly equally common on the trunk (36.54% of all FN, mean 21.52, median 11, sd=28.8) and on the lower extremities (36.52% of FN, mean 21.51, median 11, sd=30.2). MN were most common in the head and neck region in females (49.3% of all MN, mean 1.7, median 1, sd=2.8); in males, MN were nearly equally common in the head and neck region (41.2% of MN, mean 1.7, median 1, sd=2.4) and on the trunk (42.9% of MN, mean 1.8, median 1, sd=3.1) in males. UN were mostly found on the trunk in both sexes (females, 60.5% of UN, mean 1.0, median 0, sd=2.3; males, 71.9% of UN, mean 1.2, median 0, sd=3.3). The results are shown in Figure 2.
Measuring nevus densities (number of nevi per square meter) represents another method to characterize differences in the body site distribution of nevi. To achieve this, we correlated the numbers of nevi with the proportions of total body surface area (BSA) for each body region. For adults, these proportions are as follows: head 7 percent, neck 2 percent, upper arms 4 percent (each side), forearms 3 percent (each side), hands 3 percent (each side), trunk 26 percent (buttocks and genitalia excluded), thighs 9.5 percent (each side), lower legs 6 percent (each side), feet 3.5 percent (each side) . The body-site distribution of nevus densities is shown in fig. 3. For better graphical representation, we classified the densities in subgroups. The highest density of nevi (all subtypes) was found on the upper arms and on the neck. The density of FN was highest on the upper arms and forearms, of MN on head and neck, and of UN on neck and trunk. The differences of densities in different body regions were highly significant both for total nevi and for nevus subtypes (p<0.001, Friedman test).
The analysis of nevus counts with regard to age groups (decades) showed that FN, similar to total nevi, were most common in the 3rd decade of life (21-30 y) and decreased afterwards. By contrast, MN and UN were more common in older age groups. The peak of MN was found in the 6th decade (51-60 y), and the peak of UN in the 8th decade (71-80 y; p<0.01 for differences between age groups in all nevus subtypes, H test). The results are shown in fig. 4. In melanoma patients, the peak for MN was one decade earlier (5th decade; p<0.05 for differences between melanoma group and non-melanoma group, U test). Total nevi counts and FN counts in males peaked in the 2nd decade.
Several reports including the present study suggest that high nevus counts are predictive of the personal risk of melanoma. To test the hypothesis that even the readily visible nevi on the face might represent a good risk indicator, we correlated the number of facial nevi (FN, MN, UN) with total nevus counts in patients with and without a personal history of melanoma. The results are shown in fig. 5. The number of facial nevi tended to be higher in the melanoma group than in the non-melanoma group (mean 5.0 vs. 3.22 facial nevi). Regarding single age groups, these differences gained statistical significance in the 3rd and in the 6th decade (p<0.05, U test). In comparison with subjects with 0-4 facial nevi, patients with 5-10 facial nevi had a relative risk of 1.1 (95% CI 0.48; 2.51), and patients with more than 10 facial nevi had a relative risk of 2.6 (1.02; 6.43). As an interesting exception to the general trend, the number of facial nevi in the 4th decade was even slightly lower in the melanoma group than in the non-melanoma group.
We used data from a detailed UV questionnaire to explore the influence of constitutional factors and solar irradiation on the numbers of nevus subtypes. The analysis showed that patients who reported fair or red hair color in their youth had only slightly more FN, but significantly more MN and UN (Table 2). This effect was independent from the sunburn/tanning constitution, as measured by the Fitzpatrick skin type. Patients with skin types 2 and 3 had more nevi and more FN than patients with skin types 1 and 4, but this effect was statistically significant only on the level of total nevus counts (p<0.05 for differences between types 1-4; H test). By contrast, the numbers of MN and UN tended to be higher in skin types 1 and 2 and showed a decrease towards skin types 3 and 4.
To explore the personal history of sunburns, we asked for (1) "do not remember sunburn(s)," (2) "do remember sunburn(s) only generally," and (3) "do remember sunburn(s) concretely (city/country, year)." Patients from group 1 had significantly lower FN counts compared to patients from groups 2 and 3 (mean 16.8 FN vs. 57.7/63.3 FN; p<0.001, H test). For MN and UN, nevus counts in group 1 were only slightly lower than in groups 2 and 3. Patients who historically reported more occasions of solar/UV irradiation (e.g., beach stays, sun holidays, professional and recreational outdoor activities) had significantly more FN than patients with only few occasions (p<0.001, U test). On the contrary, the numbers of MN were only slightly higher and the numbers of UN were even lower in patients with more occasions of UV exposure (p<0.001 for UN, simplified linear regression).
To test if certain clinically visible signs of sun sensitivity and cumulative sun exposure might be correlated with the nevus subtype counts, we measured the number of solar ("senile") lentigines (SL), solar elastosis (SE), and interfollicular erythrosis of the neck (EIC), by semiquantitative grading (none, +,++,+++). Likewise, we assessed the number of seborrheic keratoses (SK). As a result, all four types of lesions were significantly associated with fewer FN and with more MN and UN (p<0.01, U test). However, this effect proved to be secondary to the age of the patients. Interestingly, patients who showed SE and SK at a relatively early age (SE, 21-30 y; SK, 31-60 y), had higher total nevus counts than patients without these indicators of early and intense sun exposure (p<0.01 for SE; U test).
The mean total nevus count in the present study was 56 (non-melanoma group) and 125 (melanoma group). These counts are higher than in the majority of other nevus count studies [7, 8, 9, 10, 11]. The difference is explained by the fact that we counted nevi irrespective of their size as far as they were clinically identifiable as melanocytic nevi. Most other studies only counted nevi with a diameter larger than 2 or 3 mm. Cooke et al.  demonstrated that nevus counts without a size limit were 2 to 3 fold higher than nevus counts starting at 2 mm. A restriction to nevi larger than 2 mm makes the whole-body examination more difficult and time-consuming and only represents an arbitrary division. Additional explanations for the high nevus counts in our study are the ethnic composition of the study population (mostly patients from northern Germany) and the worldwide increase the incidence of melanocytic nevi [11, 12].
The peak of total nevus counts in the 3rd decade is in accordance with other studies [9, 13, 14]. Histological studies on nevi from different age groups suggest that individual nevi follow a characteristic time-course finally leading to regression and disappearance [15, 16] (for a review, see ). Wiecker et al.  could demonstrate that moderate sun exposure in early life is already sufficient to induce higher numbers of nevi in children. However, the influence of sun and climate on nevus numbers was no longer measurable in older children and young adults . It has even been suggested that high levels of sun exposure might accelerate the natural regression of nevi .
Our study focused on morphological subtypes of melanocytic nevi. The classification by Ackerman  describes "Clark nevi," "Miescher nevi," and "Unna nevi" as nevus subtypes with fairly reproducible clinically and histological features. It has to be clarified that the Ackerman definition of Clark nevi is not identical to the ill-defined term "dysplastic nevus," as it was proposed by Clark and co-workers . The difficulties to define reliable histological and clinical criteria of "atypia" or "dysplasia" are numerous. Therefore, we regard it as a reasonable, yet provisional concept to subsume flat, predominantly junctional melanocytic lesions under a single category. These include nevi formerly designated as "common nevi," "atypical nevi," and "dysplastic nevi," respectively. As mentioned in the introduction, we changed the term "Clark nevus" to "flat nevus" (FN) to avoid confusion with the term "dysplastic nevus."
In our study, FN represented the preponderant type (91.59%), followed by MN (5.84%), and UN (2.37%). Schmoeckel , in a histological study of 678 nevi, identified 52 percent of nevi as FN, 30 percent as UN, and 10 percent as MN. However, the comparison of these figures with our clinical data is difficult, because the selection criteria for excision, e.g., for cosmetic reasons, leads to a significant bias.
The nevus subtypes exhibited significant differences regarding their age distribution. In contrast to FN and total nevus counts (3rd decade), the peak of MN was found in the 6th decade (51-60 y) and the peak of UN in the 8th decade (71-80 y). This is in part explainable by the fact that dermal nevi often produce less pigment and therefore give rise to clinical detection later than junctional nevi. However, even if FN, MN, and UN represent clinically and histologically distinct entities, a certain transition zone of intermediate lesions seems to exist. It is likely that nevi that will gain the typical morphology of MN and UN in adulthood are relatively flat at a younger age and may then be clinically diagnosed as FN.
Several studies including our own showed that patients with a personal history of melanoma have significantly more nevi than controls [8, 11, 22, 23]. The number of melanocytic nevi of an individual is therefore regarded as the most important clinical indicator of the personal melanoma risk. Garbe et al.  determined a relative melanoma risk of 3.7 in persons with 51-100 nevi and a relative risk of 7.6 in persons with more than 100 nevi compared to persons with 0-10 nevi. In our study, the counts of FN, MN, and UN were significantly elevated in the melanoma group. This important finding shows that high nevus counts of each subtype should be regarded as a personal risk marker for melanoma. The correlation between nevus counts and melanoma risk points to a constitutionally elevated predisposition for pigment cells to develop (benign and malignant) oncogenic mutational events in nevus-prone and melanoma-prone individuals. The statistical association might even more directly be explained by the fact that melanocytic nevi are facultative precursors of melanoma. Histological studies have shown that about 10-35 percent of cutaneous melanomas show remnants of nevus cells [24, 25]. These remnants often extend into the mid-dermis and are arranged in the vicinity of hair follicles. This has erroneously been taken as evidence for an elevated melanoma risk of small congenital nevi because most dermatopathologists judge adnexotropism of dermal nevus cells as suggesting a "congenital pattern" . In fact, most of these predominantly dermal nevi are postnatally acquired nevi and represent MN or UN. Together with the above-mentioned histological data, our clinical findings strongly support the notion that the risk of malignant degeneration of MN and UN is comparable to that of FN. This is an important finding because FN, due to clinically "atypical" or histologically "dysplastic" features are more readily suspected as melanoma precursors.
The results of histological studies (and the clinical experience of dermatologists) suggest that certain morphological types of melanocytic nevi are preferentially found at certain body regions. For the best of our knowledge, our study provides the first quantitative clinical data to describe the body-site distribution of nevus subtypes. The highest counts of FN were found on the lower extremities in females and on the trunk and lower extremities in males. MN were most common on the head and neck region in females and on the head and neck region and trunk in males. UN were mostly found on the trunk in both sexes. These results are in agreement with histological studies [15, 21, 26] which have shown that "bulky," predominantly dermal nevi are found mainly on the head and the upper part of the body, whereas "flat," predominantly junctional nevi are mostly located at the distal parts of the extremities. The trunk and the proximal parts of the extremities took an intermediate place in these studies. Our results further confirm that, in terms of nevus density, FN are most concentrated on the upper arms and thighs, MN on the head and neck, and UN on the neck and trunk. The preference of nevus subtypes for certain body regions is highly characteristic. Assuming that FN mostly develop from junctional melanocytes, whereas MN and UN are derived from dermally located melanocytic (stem?) cells, the latter precursor cells seem to be more prevalent on the upper parts of the body. Even if located on sun-exposed body-sites, MN and UN are possibly less dependent on UV light because UVB only reaches the uppermost parts of the dermis. On the other hand, there are lines of evidence that junctional nevi (i.e., FN) frequently exhibit UV-dependent BRAF mutations and show histological and molecular similarities to BRAF mutated melanomas . Dermal or "congenital pattern" nevi may harbor BRAF and NRAS mutations and take an intermediate place between junctional nevi and (predominantly NRAS-mutated) true congenital nevi . Interestingly, several studies have shown that melanomas of the head and neck region (lentigo maligna excluded) differ from melanomas of other body regions by a more unfavorable prognosis [29, 30, 31]. This indicates that benign and malignant melanocytic tumors exhibit site-specific morphological and proliferational characteristics, making the study of morphological subtypes and location-dependent factors an important field of future research.
We further tested if the number of facial nevi might serve as an indicator for the personal risk of melanoma. Indeed, we found that, especially in young adults, the number of facial nevi was of predictive value. In this age group, the identification of persons at risk for melanoma is of special importance for educational purposes. According to our results, patients in the first three decades showing multiple (>10) nevi on the face should be carefully instructed to undergo regular total body examinations because they carry an elevated melanoma risk.
We found that patients with skin types 2 and 3 had more FN than patients with skin types 1 and 4. By contrast, the numbers of MN and UN tended to be higher in skin types 1 and 2 and showed a decrease towards skin types 3 and 4. Moreover, in our study population, patients who reported fair or red hair color in their youth had only slightly more FN, but significantly more MN and UN than patients with dark hair. These differences indicate that MC1-R variants constituting a skin type 1/fair or red-haired phenotype, more often develop MN and UN. On the contrary, exogenous factors, especially UV light, seem to be more important in determining the numbers of FN. Again, this would support the presumption that (UV-dependent) BRAF mutations and (UV independent) NRAS mutations are differently weighted in FN and MN/UN. Previous studies have shown higher nevus counts in skin type 2 than in skin type 1 in children [17, 32, 33]. However, a clear-cut correlation between skin type and nevus counts was not found in studies on adult populations [8,9,22]. This might be explained by the fact that these studies did not differentiate between nevus subtypes. Additionally, the determination of skin types relies on historical data and is thus error-prone. The original classification by Fitzpatrick, as in our questionnaire, was based on verbal responses regarding first, moderate, unprotected noon exposure in northern latitudes for a period of 45 to 60 minutes . In later investigations, the question was often simplified to "always burn, never tan" etc., which might lead to different results.
TThe higher dependency of FN than MN/UN on UV light is also illustrated by our data concerning the personal history of solar exposure. Patients who did not remember sunburns had significantly lower FN counts compared to patients remembering sunburns, whereas for MN and UN, nevus counts were only slightly lower. Correspondingly, the group of patients who reported more outdoor activities had significantly more FN, but only slightly more MN (and even slightly fewer UN!) than patients with only fewer occasions. However, these data should not be over-interpreted because older patients (with fewer FN and more MN/UN) tended to report fewer sunburns and fewer occasions of UV irradiation in our population.
The same applies to the correlations between nevus counts and individual signs of high cumulative UV exposure, i.e., solar ("senile") lentigines, solar elastosis, and interfollicular erythrosis of the neck. We also measured seborrheic keratoses because our clinical experience in patients with dozens of seborrheic keratoses on the trunk shows that these lesions are almost always absent in the sun-protected region of the buttocks. Therefore, we regard UV light as a co-pathogen for SK. As expected, all four types of lesions were more often found in older patients who also showed higher MN and UN counts. The age profiles suggest that benign skin tumors (SL, SK) and other signs of UV exposure (SE, EIC) have their own individual age distribution and a distinct pathogenetic profile.
In summary, nevogenesis is a multifactorial process, involving constitutional and environmental factors. The influence of constitutional factors is highlighted by the correlations of skin type and hair color with the numbers of MN and UN. By contrast, the exogenous factor of solar irradiation seems to be more important for predominantly junctional nevi (FN) in younger persons than for predominantly dermal nevi (MN, UN). Moreover, the mode of sun exposure (moderate, cumulative exposure vs. sunburns) is purported to play an important role. Regarding melanoma risk, the counts of melanocytic nevi proved to be predictive for each subtype in our study. The number of facial nevi may serve as a reliable approximation to this risk in adolescents and young adults. Even if this clinical analysis of subtypes of melanocytic nevi examines a selected ethnic group of caucasians from northern Germany, it shows interesting parallels to recently identified molecular pathogenetic findings and might reflect general features of nevogenesis. The clinico-pathological classification of nevus subtypes has to be further explored on the molecular level.
References1. Unna PG. Naevi und Naevocarcinome. Berliner Klin Wochenschr 1893; 30:14-16
2. Krengel S. Nevogenesis - new thoughts regarding a classical problem. Am J Dermatopathol 2005; 27:456-465. [PubMed]
3. Dadzie OE, Goerig R, Bhawan J. Incidental microscopic foci of nevic aggregates in skin. Am J Dermatopathol 2008; 30:45-50. [PubMed]
4. Ackerman A, Magana-Garcia M. Naming acquired melanocytic nevi. Am J Dermatopathol 1990; 12:193-209. [PubMed]
5. Witt C, Igl B, Krengel S. Bedeutung des Sonnenverhaltens für die Entstehung melanozytärer Nävi. Akt Dermatol 2006; 32:1-6
6. Lund CC, Browder NC. The estimation of areas of burns. Surg Gynecol Obstet 1944; 79: 352-358
7. Bataille V, Grulich A, Sasieni P, Swerdlow A, Newton Bishop J, McCarthy W, Hersey P, Cuzick J. The association between naevi and melanoma in populations with different levels of sun exposure: a joint case-control study of melanoma in the UK and Australia. Br J Cancer 1998; 77:505-510. [PubMed]
8. Garbe C, Buttner P, Weiss J, Soyer HP, Stocker U, Kruger S, Roser M, Weckbecker J, Panizzon R, Bahmer F, Tilgen W, Guggenmoos-Holzmann I, Orfanos C. Associated factors in the prevalence of more than 50 common melanocytic nevi, atypical melanocytic nevi, and actinic lentigines: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society. J Invest Dermatol 1994; 102:700-770. [PubMed]
9. Mackie RM, English J, Aitchinson TC, Fitzsimons CP, Wilson P. The number and distribution of benign pigmented moles (melanocytic naevi) in a healthy British population. Br J Dermatol 1985; 113:167-174. [PubMed]
10. Naldi L, Lorenzo IG, Parazzini F, Gallus S, La Vecchia C. Pigmentary traits, modalities of sun reaction, history of sunburns, and melanocytic nevi as risk factors for cutaneous malignant melanoma in the Italian population: results of a collaborative case-control study. Cancer 2000; 88:2703-2710. [PubMed]
11. Bauer J, Garbe C. Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data. Pigment Cell Res 2003; 16:297-306. [PubMed]
12. Cooke KR, Spears GF, Skegg DC. Frequency of moles in a defined population. J Epidemiol Community Health 1985; 39:48-52. [PubMed]
13. Armstrong BK, deKlerk NH, Holman CD. Etiology of common acquired melanocytic nevi: constitutional variables, sun exposure, and diet. J Natl Cancer Inst 1986; 77:329-335. [PubMed]
14. Nicholls EM. Development and elimination of pigmented moles, and the anatomical distribution of primary malignant melanoma. Cancer 1973; 32:191-195. [PubMed]
15. Lund H, Stobbe G. The natural history of the pigmented nevus; factors of age and anatomic location. Am J Pathol 1949; 25:1117-1155. [PubMed]
16. Maize J, Foster G. Age-related changes in melanocytic nevi. Clin Exp Dermatol 1979; 4:49-58. [PubMed]
17. Wiecker T, Luther H, Buettner P, Bauer J, Garbe C. Moderate sun exposure and nevus counts in parents are associated with development of melanocytic nevi in childhood. Cancer 2003; 97: 628-638. [PubMed]
18. Kelly JW, Rivers JK, MacLennan R, Harrison S, Lewis AE, Tate BJ. Sunlight: a major factor associated with the development of melanocytic nevi in Australian schoolchildren. J Am Acad Dermatol 1994; 30:40-48. [PubMed]
19. Harth Y, Friedman-Birnbaum R, Linn S. The influence of cumulative sun exposure on the prevalence of common acquired nevi J Am Acad Dermatol 1992; 27:21-24. [PubMed]
20. Greene MH, Clark WH Jr, Tucker MA, Elder DE, Kraemer KH, Fraser MC, Bondi EE, Guerry D, Tuthill R, Hamilton R, LaRossa D. Precursor nevi in cutaneous malignant melanoma: a proposed nomenclature. Lancet 1980; 2(8202):1024. [PubMed]
21. Schmoeckel C. Classification of melanocytic nevi: do nodular and flat nevi develop differently? Am J Dermatopathol 1997; 19:31-34. [PubMed]
22. Kennedy C, Bajdik CD, Willemze R, De Gruijl FR, Bouwes Bavinck JN. The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses, seborrheic warts, melanocytic nevi, atypical nevi, and skin cancer. J Invest Dermatol 2003; 120:1087-1093. [PubMed]
23. Swerdlow AJ, English J, Mackie RM, ODoherty CJ, Hunter JA, Clark J. Benign nevi associated with high risk of melanoma. Lancet 1984; 2:168. [PubMed]
24. Crucioli V, Stilwell J. The histogenesis of malignant melanoma in relation to pre-existing pigmented lesions. J Cutan Pathol 1982; 9:396-404. [PubMed]
25. Lopansri S, Mihm MC Jr. Clinical and pathological correlation of malignant melanoma. J Cutan Pathol 1979; 6:180-194. [PubMed]
26. Winkelmann R, Rocha G. The dermal nevus and statistics. Arch Dermatol 1962; 86:100-105. [PubMed]
27. Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, Redman B, Thomas NE, Gruber SB. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res 2006; 16:267-273. [PubMed]
28. Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007; 127:179-182. [PubMed]
29. Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the Surveillance, Epidemiology, and End Results (SEER) program. Arch Dermatol 2008; 144:515-521. [PubMed]
30. Golger A, Young DS, Ghazarian D, Neligan PC. Epidemiological features and prognostic factors of cutaneous head and neck melanoma: a population-based study. Arch Otolaryngol Head Neck Surg 2007; 133:442-447. [PubMed]
31. Hoersch B, Leiter U, Garbe C. Is head and neck melanoma a distinct entity? A clinical registry-based comparative study in 5702 patients with melanoma. Br J Dermatol 2006; 155:771-777. [PubMed]
32. Gallagher RP, McLean DI, Yang CP, Coldman AJ, Silver HK, Spinelli JJ, Beagrie M. Suntan, sunburn, and pigmentation factors and the frequency of acquired melanocytic nevi in children. Similarities to melanoma: the Vancouver Mole Study. Arch Dermatol 1990; 126:770-776. [PubMed]
33. Nicholls EM. Genetic susceptibility and somatic mutation in the production of freckles, birthmarks and moles. Lancet 1968; 1(7533):71-73. [PubMed]
34. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol 1988; 124:869-871. [PubMed]
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