Development Of Melanocytic Nevi Research Articles

Abstract 1037: Progression from melanocytic nevi to melanoma is associated with increased genomic mutations in a UV-induced mouse model of human melanoma

Abstract Melanoma is the deadliest form of skin cancer with approximately 132,000 cases worldwide each year. Benign melanocytic nevi are nearly universal, and although progression of nevi to melanoma is very rare, 20-50% of melanoma appear to arise from a pre-existing nevus. UV exposure, particularly childhood sunburn, is believed to play an important role in the development of melanocytic nevi and melanoma, but the exact mechanism is unknown. Alterations in MAPK pathway genes, especially NRAS and BRAF, are common in both benign nevi and melanoma, but approximately 1/3 of melanomas do not have an identified driver mutation. Studying nevus initiation and progression prospectively in the human population is impractical due to the long latency to progression and repeated UV exposures Our laboratory has developed a hepatocyte growth factor (HGF) genetically engineered mouse model with “humanized” junctional distribution of melanocytes on an iDCT-GFP background with melanocyte-specific GFP expression, allowing melanocytic lesions to be tracked through percutaneous GFP imaging. Following a single relevant dose of UV modeling childhood sunburn, HGF iDCT-GFP develop discrete, small melanocytic lesions consistent with nevi. Most nevi remain stable over the lifetime of the mouse, but around 1 in 30 progress to melanoma usually starting at 6-12 months. The melanocytic lesions are histologically similar to human nevi and melanoma, label with melanocyte markers and tumors are transplantable into syngeneic mice. Melanomas that arise in the model are heterogeneous and include radial growth phase and vertical growth phase tumors and sometimes metastasize to liver and lung. Exome sequencing of 28 nevi and melanomas show that vertical growth phase melanomas have approximately 3x more mutations than radial growth phase melanomas or nevi. The increased number of mutations in vertical growth phase tumors is due to an increase in C>T transitions despite the lack of additional UV exposure. Interestingly, melanocytic nevi and melanomas with DNA repair pathway mutations average 3x more mutations than lesions without mutations in these pathways. Melanomas sometime contain mutations in hotspot locations from human melanomas, including GNAQ, but most do not have a previously identified dominant driver. Genes potentially involved in the initiation of melanocytic lesions or progression to aggressive melanomas and relevant to human melanoma have been identified and are being functionally tested using CRISPR to introduce point mutations or knock out genes and in vitro skin reconstitution assays. Identification of novel drivers and pathways involved in non-BRAF, non-NRAS melanoma has the potential to uncover biomarkers and new therapeutic targets to improve clinical outcomes for melanoma patients. Citation Format: Helen Michael, Chi-Ping Day, Howard Yang, Aleksandra Michalowski, Maxwell Lee, Glenn Merlino. Progression from melanocytic nevi to melanoma is associated with increased genomic mutations in a UV-induced mouse model of human melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1037. doi:10.1158/1538-7445.AM2017-1037

Abstract B33: Langerhans cells prevent melanocytic nevus development and transformation in mice.

Abstract The function of Langerhans cells (LCs) in the skin immune system is unclear, and a matter of intense debate. In different mouse models LCs have been shown to induce antitumor immunity or promote skin squamous cell carcinoma (SCC). Their role in the control or promotion of melanoma is not known. We assessed LC's role in the development of DMBA-TPA induced pigmented benign and transformed lesions in a novel mouse model. Transgenic HuLang-DTA+/- C57Bl/6 mice, which selectively ablate epidermal LCs, were crossed with C3H/HeN mice to generate F1 LC knockout (KO) and WT littermate controls. LC-KO mice developed 40% more and 2-fold larger melanocytic lesions than WT. Cell suspensions from LC-KO pigmented skin lesions contained increased CD4+ Foxp3+ regulatory T cells and CD11b-/loGr-1hi cells, consistent with an immunosuppressive microenvironment. CD11c+CD11b+Ly6C+ APCs or MHCII+ cell numbers were fewer in lesions from LC-KO as compared to WT mice. Nests of melanocytic cells were observed at a higher frequency in draining lymph nodes (dLNs) from LC-KO as compared to WT; DLN cells contained increased numbers of TRP2+ cells and routinely gave rise to proliferative melanocytic cell lines. Real-time PCR analysis of epidermal cDNA from TPA treated LC-KO, as compared to WT, demonstrated a profound loss of IL-10, IL-12p35 and IL-12p40, indicating LCs as the major source. Further, IL-23 steady state levels in the epidermis of LC-KO are increased greater than 3-fold over WT, indicating that LCs normally suppress keratinocyte production of IL-23. Thus, in contrast to SCC, LCs inhibit development of benign and metastatic pigmented tumors. This novel murine model will be useful in elucidating transformation mechanisms and identifying novel therapeutic targets that may prevent metastatic melanoma. Citation Format: Tahseen H. Nasti, Yuko Tsuruta, Kris McKay, Mohammad Athar, Craig Elmets, Laura Timares. Langerhans cells prevent melanocytic nevus development and transformation in mice.. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B33. doi:10.1158/1538-7445.CHTME14-B33

MTORC1 Activation Blocks BrafV600E-Induced Growth Arrest but Is Insufficient for Melanoma Formation

Braf(V600E) induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in Braf(V600E) melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100, which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 (Lkb1) loss abrogates growth arrest of Braf(V600E) melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in Braf(V600E) melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis.

Neonatal blue light phototherapy increases café-au-lait macules in preschool children.

Neonatal blue light phototherapy (NBLP) is an effective treatment for hyperbilirubinaemia. Concerning the influence on melanocytic nevi, conflicting studies have been published. To assess the role of NBLP according to the incidence of melanocytic nevi in preschool children, a cohort of 104 5- to 6-year-old children were included. The case group consisted of 52 NBLP-exposed children, while the control group (n = 52) never had NBLP and was matched regarding age, gender, gestational age and skin phototype. Six dizygotic twins were included with one twin having received NBLP, respectively. The following parameters were recorded: nevi count, presence of freckles, café-au-lait macules, skin phototype and previous history of sun exposure. There was no significant association between nevi count and exposure to NBLP (median nevi count 17.0 compared to 18.5 in controls). No significant difference was also found in the dizygotic twin pairs with a median nevi count of 10.0 (with NBLP) compared to 14.5 (without NBLP). However, a significantly higher prevalence of café-au-lait macules was found in children with NBLP (mean count 0.5) than in children without NBLP (mean count 0.2; p = 0.001). Significant predictors for the number of melanocytic nevi included skin phototype, sun exposure and vacations in the South. In this study, NBLP had no significant influence on the development of melanocytic nevi, but on café-au-lait macules which was a new finding. Differences with comparable studies regarding age, differentiation between nevi and other pigmented lesions as well as dose and type of NBLP need to be taken into account for further investigations.

Is Spontaneous Disappearance of Nevus Depigmentosus Possible?

Dear Editor: Nevus depigmentosus (ND) is characterized by a congenital hypopigmented macule or patch. The pathophysiology of ND is poorly understood, but likely associated with a functional defect in melanosome transfer from melanocytes to keratinocytes1. ND is known to remain generally stable in size and distribution throughout life1. Herein, we describe a case of a 6-year-old boy whose ND disappeared, suggesting the possibility of spontaneous resolution of ND. A 10-month-old male was brought to our clinic because of whitish patches on his right leg that had been present since his birth. Physical examination revealed hypopigmented patches on the medial side of right thigh (Fig. 1a). A diffuse bluish patch that was suspected to be an aberrant Mongolian spot surrounded the hypopigmented areas. A 2-mm punch biopsy of the hypopigmented patches and adjacent perilesional normal skin at 1 cm from margin was performed. There were no remarkable findings on H&E staining (Fig. 2a). Fontana-Masson staining showed decreased epidermal pigmentation in the lesional skin compared to the perilesional normal skin (Fig. 2b). There was no difference in the number of NKI/beteb positive melanocytes between the lesional and perilesional normal skin (Fig. 2c). These findings were consistent with ND. The patient did not receive any treatment and was lost to follow-up until his recent revisit 6 years later. At that time, he returned with a facial mobiliform eruption, accompanied by fever and conjunctival injection, and was diagnosed with erythema infectiosum. Interestingly, during physical examination, it was noted that the previous ND and the surrounding aberrant Mongolian spot had completely disappeared (Fig. 1b). The patient's parents did not recall the time of the ND disappearance. Fig. 1 Spontaneous disappearance of hypopigmented macules and patches. (a) A 10-month-old male presented with hypopigmented macules and patches on his right thigh in linear configuration since birth. A diffuse bluish patch that was suspected to be an aberrant ... Fig. 2 Histological findings. (a) There were no remarkable findings on H&E staining. (b) Fontana-Masson staining showed decreased epidermal pigmentation in the lesional skin compared to the perilesional normal skin. (c) There was no difference in the ... Spontaneous resolution of ND has never been reported. However, it should be noted that there has been no epidemiological study regarding the fate of ND. Moreover, there have been several reports suggesting the possibility that the functional defect of the melanocytes in ND is reversible2,3. Bardazzi et al.2 described the development of lentigines within ND after narrow band ultraviolet B exposure. They suggested the possibility of partial activation of melanosome transfer, resulting in overproduction of melanin within ND. Oiso et al.3 reported a case of acquired junctional melanocytic nevus development in ND. These cases suggest that melanocytes in ND could transform from a functionally defective stage to an active stage or shift to other forms such as nevus cells. Interestingly, in our case, the ND and Mongolian spots were coexistent at the initial visit and both had disappeared at the next visit. The possible relationship between Mongolian spots and spontaneous regression of ND could be suspected. There was no confirmative diagnosis of ND. It is important to consider the other hypopigmenting conditions, such as postinflammatory hypopigmentation or hypomelanosis of Ito4. Because the lesion was present from birth and he did not have any history of inflammation on the hypopigmented lesion, postinflammatory hypopigmentation could be differed from our case. Hypomelanosis of Ito consists of hypopigmented zones or spots with irregular borders, whorls, patches, or linear streaks with various patterns of distribution5. It follows the lines of Blaschko that represent a peculiar pattern of distribution. In addition, hypomelanosis of Ito usually encounter the extracutaneous manifestation. Reviewed in aspect of distribution of lesions and extracutaneous symptoms, we thought that hypomelanosis of Ito was less likely in our case. Therefore, considering the congenital hypopigmented macules, distribution, and other clinical manifestations, the hypopigmented macules and patches were most likely ND. In conclusion, our case suggests the possibility that ND could disappear. An epidemiological study of ND with long term follow up is further needed to know if ND could disappear, as in our case, or is persistent throughout life.

Neonatal Blue Light Phototherapy and Melanocytic Nevi: A Twin Study

Neonatal blue light phototherapy (NBLP) has been widely and successfully used for the treatment of neonatal jaundice to reduce the plasma concentration of bilirubin and, hence, to prevent kernicterus. Only a few and controversial data are available in the literature as to how NBLP influences melanocytic nevus development. Our goal was to conduct a twin study with the aim of better understanding the role of NBLP in melanocytic nevus development. We also investigated the roles of other environmental and constitutional factors in nevus formation. Fifty-nine monozygotic and dizygotic twins were included in this cross-sectional study. One of the twin members received NBLP, and the other did not. A whole-body skin examination was performed to determine the density of melanocytic skin lesions. The prevalence of benign pigmented uveal lesions was evaluated during a detailed ophthalmologic examination. A standardized questionnaire was used to assess data relating to constitutional, sun-exposure, and other variables. To search for possible gene-environmental interactions involved in the appearance of pigmented lesions, the melanocortin 1 receptor variants and the I439V polymorphism of histidine ammonia-lyase genes were also determined in the enrolled twins. NBLP was associated with a significantly higher prevalence of both cutaneous and uveal melanocytic lesions. No association was found between the examined gene polymorphisms and the number of pigmented alterations in the examined study group. Our data suggest that NBLP could well be a risk factor for melanocytic nevus development. Phototherapy with blue-light lamps is a standard and essential therapeutic modality in neonatal care; therefore, additional in vivo and in vitro studies are necessary to establish its potential long-term adverse effects.

Neonatal UVB exposure accelerates melanoma growth and enhances distant metastases in Hgf‐Cdk4R24C C57BL/6 mice

Genetically engineered mouse models offer new opportunities to experimentally investigate the impact of UV on melanoma pathogenesis. Here we irradiated a cohort of newborn 15 Hgf-Cdk4(R24C) mice on the pigmented C57BL/6 background with one erythemogenic dose of 6 kJ/m(2) UVB and compared the development of nevi and melanoma with a cohort of 30 untreated Hgf-Cdk4(R24C) mice. Neonatal UVB exposure decreased the latency and accelerated the growth of primary melanomas resulting in a significantly decreased time from melanoma onset to melanoma-related death (61 days vs. 96 days). Interestingly, we did not observe differences in the development of melanocytic nevi. Histopathological investigations revealed that UVB irradiation shifted the spectrum of melanomas toward a more aggressive phenotype with increased tumor cell proliferation, invasive growth and enhanced angiogenesis. Accordingly, we observed distal melanoma metastases in the lungs more frequently in the UV-irradiated than in the untreated cohort of Hgf-Cdk4(R24C) mice (73% vs. 47%). UVB-induced melanomas only contained very few infiltrating immune cells and expressed very low levels of proinflammatory chemokines. Taken together, our results demonstrate that neonatal UVB exposure promoted the early appearance of rapidly enlarging primary melanomas in Hgf-Cdk4(R24C) C57BL/6 mice which showed enhanced invasive and metastatic behaviour without a persistent tumor-associated inflammatory response. The preferential impact of UVB irradiation on the progression of melanoma without an effect on the development of nevi supports the hypothesis that the molecular targets of UVB are involved in bypassing the proliferative arrest of transformed melanocytes without alerting a cellular immune response.

Formation mechanism of melanocytic nevi

Melanocytic nevi are common in clinic, while its mechanism is unknown yet. Recent studies on relation between eruptive melanocytic nevi and immunosuppressive agents have shown that the formation of melanocytic nevi is relevant with immunosuppression. Melanocyte-stimulating hormone (MSH)-α plays a certain role in the development of melanocytic nevi by up-regulating the expression of microphthalmia-associated transcription factor (Mitf) and promoting the proliferation of melanocytes through cAMP pathway. Also, MSH-α together with immunosuppressive agents could affect Langerhans cells,T cells and expressions of cytokines such as interleukin (IL)-10, IL-12, etc., possibly exert upon MAPK pathway, up-regulate the expression of Mitf, thereby result in the formation of melanocytic nevi. Key words: Melanocytes ; Nevus ; Alpha-MSH ;

New insights into nevogenesis: In vivo characterization and follow-up of melanocytic nevi by reflectance confocal microscopy

Development of melanocytic nevi is a complex process. The aim of the study was to characterize the in vivo confocal microscopy patterns and histopathologic correlates of melanocytic nevi. In addition, for the first time, confocal follow-up of characteristic nevi was performed documenting histologic changes in nevi. For the correlation study, 33 melanocytic nevi showing characteristic dermatoscopic patterns were studied by confocal microscopy. For the follow-up study 20 nevi were monitored for 12 to 18 months. Reticular nevi showed two different confocal patterns, ringed and meshwork, mostly corresponding to lentiginous and nested junctional patterns, respectively. Globular nevi presented large junctional clusters, whereas cobblestone nevi were constituted by dermal dense melanocytic clusters. Homogeneous nevi did not show distinctive confocal and histopathologic findings. Nevi with a rim of globules presented a meshwork pattern with junctional clusters at the periphery. At the confocal follow-up study all lesions showed limited dynamic changes resulting in stable dermatoscopic and confocal patterns, but 3 globular nevi with junctional nests at baseline evolved into reticular-meshwork pattern nevi with peripheral rim of globules-junctional nests. Longer confocal follow-up of more melanocytic nevi is required to confirm this theory and to validate our preliminary findings. A model explaining the nevus classification and patterns of evolution of nevi observed in the study was proposed.

Melanocytic Nevus Development in Colorado Children Born in 1998

To describe the development of nevi from 3 to 8 years of age in a birth cohort of children in Colorado. Longitudinal observational study. Large managed care organization and university and private primary care practices. Annual convenience samples of children born in 1998 (range, n = 137 to n = 870) (participation rates, 18.8%-76.0%). We recruited children through the managed care organization, private primary care practices, and community settings. Total whole body nevus counts, counts by nevus diameter (< 2, 2 to < 5, or > or = 5 mm), and counts for chronically and intermittently exposed body sites. Non-Hispanic white children had significantly more nevi than did other racial/ethnic groups and developed an average of 4 to 6 new nevi per year from 3 to 8 years of age. Non-Hispanic white boys had significantly more nevi than did girls beginning at 6 years of age (median, 21 [interquartile range, 28] vs 17 [17]; P = .002). This difference was due to nevi of less than 2 mm and nevi in chronically exposed body sites. Development of new nevi leveled off in chronically exposed body sites at 7 years of age and at a higher level for boys than girls. Children in Colorado developed more small nevi and fewer large nevi compared with children in other regions of the world, highlighting the importance of studying nevus development in various locations where sun exposure patterns and behavioral norms vary. The sex difference in nevus development could be owing to variation in sun exposure and/or a biological predisposition of boys to develop more nevi. Studies of nevus development can aid in the understanding of the complicated relationship between nevus development and malignant melanoma.

Melanocytic Nevi in 2783 Children and Adolescents in Turkey

This study investigated the numbers of melanocytic nevi in Turkish children and adolescents. The research was conducted on 2783 subjects (age range, 7-14 yrs) at three elementary schools in Malatya, Turkey (latitude 38 degrees N). Numbers of melanocytic nevi per subject were counted using a standard international protocol. Comparisons were made with subjects categorized according to age, sex and skin type. The mean melanocytic nevus count was 1.07 +/- 2.37. A significant positive correlation was found between nevus count and age (p < 0.001). The mean count for boys was significantly higher than that for girls (p < 0.001). Subjects with skin type II had a higher mean melanocytic nevus count than the other three groups. This is the first study related to numbers of melanocytic nevi in Turkey. The findings reveal that Turkish children and adolescents have few melanocytic nevi compared to those elsewhere in the world. In line with previous reports on other populations, analysis showed that older age, skin type II, and male sex are associated with higher melanocytic nevus counts. The results underline the importance of ethnic background in melanocytic nevus development.

The Relation between Patterns of Vacation Sun Exposure and the Development of Acquired Melanocytic Nevi in German Children 6-7 Years of Age

Sun exposure is the main environmental risk factor for the development of melanocytic nevi. Although the general association is not disputed, the interplay between intense intermittent and the cumulative amount of sun exposure in defining the promoting effect on melanocytic nevus development is an area of debate. Trained staff members ascertained total body counts of melanocytic nevi in a cross-sectional study of 2,189 children 6-7 years of age who were recruited in two German centers in 2002. Their parents provided information about a variety of exposure factors. The distribution of melanocytic nevi was skewed markedly to the right; therefore, a negative binomial regression model provided the appropriate framework for a multivariable analysis. A steep gradient with respect to the (adjusted) number of melanocytic nevi was apparent only for the frequency of vacation episodes associated with sun exposure in areas with an intense ultraviolet radiation. In contrast, no such gradients were found for the cumulative duration of vacation sun exposure in such areas or for any variable related to vacation sun exposure in areas with a low ultraviolet radiation. This observation supports the hypothesis that intermittent exposure to high doses of ultraviolet radiation plays an especially important role in nevus development.

Ultraviolet Radiation at Places of Residence and the Development of Melanocytic Nevi in Children (Australia)

To investigate the relationship between ambient ultraviolet radiation (UV) exposure and number of melanocytic nevi in children. A longitudinal study of nevi was conducted in 1614 children in Perth, Australia. Children had nevi counted on the back, face and arms at ages 6, 10, and 12 years. Erythemally effective UV irradiance was used to estimate ambient exposure from their places of residence before entry to the study at age 6 years. Data on UV radiation were derived from satellite measurements of ozone and atmospheric reflectivity. At baseline, the response rate was 70%. At age 10, 90% of those recruited had nevus counts and at age 12, 69%. Children who had migrated to Perth from geographical locations with higher erythemal irradiance had, on average, 1.34 (95% confidence interval, 1.16-1.54) times as many nevi on the back at age 6, 1.29 (1.13-1.49) as many at age 10 and 1.10 (0.92-1.30) times as many at age 12. No significant associations were seen for the face or arms. Ambient solar UV exposure in early childhood is positively associated with number of nevi and nevi develop soon after exposure to sunlight.

Sun Protection and the Development of Melanocytic Nevi in Children

Childhood sun exposure causes nevi (and melanoma), but there is little evidence regarding the effectiveness of sun protection strategies on the number of nevi. We previously found that boys but not girls receiving a school-based sun protection program had fewer nevi on their backs than controls. Here, we investigated whether specific program components (encouraging children to stay indoors in the middle of the day during summer, to wear clothing while outdoors, and to use sunscreen) were associated with fewer nevi. An observational analysis was done on data from a sun protection trial in 1,623 children in Perth, Australia. The outcome was number of nevi on the back 6 years after baseline, when the children were 12 years old. Information on sun protection was obtained by questionnaires 4 and 6 years after baseline. The data were analyzed by mixed-effects linear regression. The time spent outdoors between 11 a.m. and 2 p.m. and the proportion of total time outdoors that was between these hours were positively associated with number of nevi. Ratios of mean counts for doubling the respective measures were 1.09 [95% confidence interval (95% CI), 1.05-1.12] and 1.10 (95% CI, 1.05-1.14). Children whose backs were covered <70% of the time while outdoors had 1.53 (95% CI, 1.34-1.75) times more nevi than children whose backs were always covered. Using sunscreen on the back when it was uncovered was not associated with number of nevi (P = 0.59). Children who stayed indoors in the middle of the day and wore clothing while outdoors had fewer nevi.

The Effect of a School-Based Sun Protection Intervention on the Development of Melanocytic Nevi in Children: 6-Year Follow-up

Because nevi share risk factors with melanoma and are strong risk factors for melanoma, they are suitable biomarkers for evaluating sun protection programs. Kidskin was a trial of a school-based sun protection program in Western Australia that included high and moderate intervention groups and a control group. Schools were assigned nonrandomly to groups. The primary outcome was number of nevi on the back. Nevi were counted at baseline, after 4 years intervention and again 2 years later. Linear growth models, allowing for correlated data within schools and children were fitted to the data. The primary analysis included 639 control children, 414 in the moderate and 355 in the high intervention group. Compared with the control group, the relative increase in number of nevi on the back was 0.89 (95% confidence interval, 0.81-0.99) for the high intervention group and 0.94 (95% confidence interval, 0.86-1.04) for the moderate group (P = 0.09). In subgroup analyses of nevi on the back, the association was stronger in boys (P < 0.001) than in girls (P = 0.7), although the test for interaction was not significant (P = 0.11). For the chest, examined in boys, the associations were similar to that for nevi on the back in boys. Associations were weak for nevi on the face and arms (P = 0.2); for this site, there was weak evidence of heterogeneity by sex. Overall, there was weak evidence that the Kidskin intervention reduced the number of new nevi over a 6-year period, but there was stronger evidence of an effect on the trunk in boys.

Topical application of dimethylbenz[ a]anthracene results in the generation of multiple melanocytic nevi in C3H/HeN mice

Melanocytic nevi are a common dermatological problem for which there are few in vivo models. It has been postulated that environmental factors contribute to their development. Experiments were therefore conducted to determine whether application of dimethylbenz[ a]anthracene (DMBA) to the skin of mice would result in the development of melanocytic nevi. One hundred microliters of a 0.1%, 0.5%, or 1.0% solution of DMBA was applied to the dorsal skin of C3H/HeN mice. The mice were then observed for the appearance of pigmented lesions. Histological examination revealed perifollicular accumulations of nevus cells, which were S-100-protein and HMB-45-positive, confirming their melanocytic origin. Pigmented lesions did not occur in animals treated with vehicle alone. Dose response studies revealed both greater numbers of nevi and lesions with larger diameters as the dose of DMBA was increased from 0.1% to 0.5%. In no instance was an invasive melanoma observed even after 40 weeks. The fact that melanocytic nevi can be produced by topical application of DMBA suggests that xenobiotics may play a previously unrecognized role in the development of this common benign neoplasm. Because this is one of the only animal models for melanocytic nevi, further examination of this model may facilitate identification of the molecular and biochemical mechanisms that lead to the development of pigmented nevi and the factors that promote their evolution into invasive melanomas.

The Influence of Painful Sunburns and Lifetime Sun Exposure on the Risk of Actinic Keratoses, Seborrheic Warts, Melanocytic Nevi, Atypical Nevi, and Skin Cancer

Painful sunburns are implicated in the pathogenesis of squamous cell carcinoma, basal cell carcinoma, and malignant melanoma. Chronic exposure to ultraviolet radiation is known as the most important risk factor for the development of actinic keratoses and squamous cell carcinoma. The purpose of the study was to assess the effect of painful sunburns and lifetime sun exposure on the development of actinic keratoses and seborrheic warts in relation to the development of squamous cell carcinoma and basal cell carcinoma, and on the development of melanocytic nevi and atypical nevi in relation to the development of malignant melanoma. We made use of a cohort of 966 individuals who participated in a case-control study to investigate environmental and genetic risk factors for skin cancer. Exposure measurements for sunlight were collected and actinic keratoses, seborrheic warts, melanocytic nevi, and atypical nevi were counted. Relative risks were estimated using exposure odds ratios from cross-tabulation. Multivariate logistic regression was used to adjust for potential confounders. The recall of painful sunburns before the age of 20 y was associated with an increased risk of squamous cell carcinoma, nodular basal cell carcinoma, and multifocal superficial basal cell carcinoma as well as actinic keratoses. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.5 (0.97; 2.3); 1.6 (1.1; 2.2); 2.6 (1.7; 3.8); and 1.9 (1.4; 2.6) for the three types of nonmelanoma skin cancer and actinic keratoses, respectively. Painful sunburns before the age of 20 y were also associated with an increased risk of malignant melanoma and the development of its precursors, melanocytic nevi and atypical nevi. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.4 (0.86; 2.1); 1.5 (1.1; 2.0); and 1.4 (0.88; 2.3) for malignant melanoma and the two types of precursors, respectively. Lifetime sun exposure was predominantly associated with an increased risk of squamous cell carcinoma (p-value for trend=0.03) and actinic keratoses (p-value for trend <0.0001) and to a lesser degree with the two types of basal cell carcinoma. By contrast, lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma, despite the fact that lifetime sun exposure did not diminish the number of melanocytic nevi or atypical nevi. Neither painful sunburns nor lifetime sun exposure were associated with an increased risk of seborrheic warts.

Moderate sun exposure and nevus counts in parents are associated with development of melanocytic nevi in childhood: a risk factor study in 1,812 kindergarten children.

Melanocytic nevi have been identified as the most important risk factor for cutaneous melanoma. Sun exposure, sunburns, and light pigmentation have been found to be associated with their development in childhood. To the authors' knowledge, nevus proneness of parents and the exact type of ultraviolet (UV) exposure have not yet been investigated in this context. The authors' objective was to determine independent risk factors and their impact for nevus development in childhood. The current study was conducted by two university departments of dermatology in 49 public nursery schools in Stuttgart, Germany and in 38 public nursery schools in Bochum, Germany. The cross-sectional study included 1,812 children aged 2-7 years and their parents. Total body nevus counts in children, assessment of pigmentary features, and nevus counts on the arms of parents were performed. Parents underwent a standardized interview concerning national origin and lifestyle features, as well as habits and magnitude of sun exposure of children. Analysis was performed by multivariate linear regression analysis and by multiple logistic regression analysis. The number of nevi was found to steadily increase with age from a median of 3 at age 2 years to 19 at age 7 years (P < 0.0001). High numbers of nevi in children were associated with the number of weeks on sunny holidays, outdoor activities at home, skin type, facial freckling, ethnicity of parents, and the number of nevi on the arms of parents. Previously experienced sunburns failed significance (P = 0.0620). The authors found a strong association between nevus development in children and the number of parental moles, which most likely points to an inherited factor. Moderate sun exposure such as outdoor activities during a German summer without sunburns seemed to be sufficient for induction of melanocytic nevi. The authors believe that these findings will have direct impact on concepts for preventive strategies.

Development of melanocytic nevi in the first three years of life.

Extract: Interest in melanocytic nevi (moles) stems from their clinical, histologic, and epidemiologic association with melanoma. Few studies of nevi have been longitudinal (1,2), and all, apart from our own (3), have involved subjects 3 years old or older. Hence, little is known about the age at which nevi begin to develop. We compared rates of development of nevi from birth to 3 years of age in two cohorts of Caucasian children of similar ethnicity from the contrasting climates of Townsville, Australia [19° S; high levels of ambient UV radiation (4)], and Glasgow, U.K. [55° N; low levels of ambient UV radiation (5)]. The Australian cohort was recruited by approaching postpartum women at three maternity hospitals in Townsville during September and October 1994; 96.7% of the eligible mothers participated, resulting in a cohort of 115 babies of European ancestry. Scottish neonates were recruited from October 1993 through August 1994 by inviting postpartum women at the Queen Mother's Hospital, Glasgow, to participate in a randomized intervention trial focused on sun avoidance in infancy (consent rate for parents at Queen Mother's Hospital, Glasgow = 97.4%). From the latter group, only control subjects (no intervention; n = 157) were included in this study.

Increase of Melanocytic Nevus Counts in Children During 5 Years of Follow-up and Analysis of Associated Factors

To investigate nevus development in childhood and to examine causative related factors such as pigment phenotype and the role of sun exposure in the development of melanocytic nevi. Nevus counts were performed in kindergarteners (n = 866) before the age of 7 years and again 5 years later (n = 377). Eligible for analysis were 357 children who were examined twice. Possible related factors were searched for by standardized interviews with parents. The mean number of nevi measuring 1 mm or more was 9 in the first examination and the number measuring 2 mm or more, 4. Five years later, the mean number of nevi measuring 1 mm or more was 40 and the number measuring 2 mm or more was 16. Children with poor sun tolerance had statistically significant more nevi (relative risk, 3.7;95% confidence interval, 1.9-7.2). The presence of freckles was a strong predictor for a high increase of melanocytic nevi (relative risk, 2.1; 95% confidence interval, 1.3-3.3). The number of days per year with intensive solar exposure was an independent prognostic factor. The relative risk for the development of melanocytic nevi was increased by a factor of 1.6 in children who had more than 21 days of intensive sun exposure per year (95% confidence interval, 1.0-2.5). The development of melanocytic nevi in childhood is strongly related to characteristics of pigmentation associated with poor sun tolerance. In addition, we found evidence for the influence of UV radiation on the number of acquired melanocytic nevi in childhood.