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PubMed1991

HMB-45 staining of dysplastic melanocytic nevi in melanoma risk groups.

To evaluate the hypothesis that reactivity of the intradermal component of melanocytic nevi to the monoclonal antibody HMB-45 correlates with melanoma risk, dysplastic compound melanocytic nevi were examined for expression of the HMB-45 epitope in three subject groups differing in epidemiological risk for melanoma. The study groups consisted of 10 subjects with dysplastic nevi and a personal history of melanoma, 25 subjects with dysplastic nevi and a history of melanoma in one or more first degree relatives, and 15 population control subjects with sporadic dysplastic nevi. For each case, sections from one lesion, immunohistochemically processed for HMB-45 binding, were evaluated by two pathologists without knowledge of the clinical data. Of all dysplastic nevi, 98% showed diffusely positive cytoplasmic staining of the junctional nevomelanocytes and 90% had such positive staining of those cells within the superficial dermis. Nevus cells within the deeper dermis did not stain positively in any case. Furthermore, the data showed no differences in frequency, pattern, or intensity of HMB-45 reactivity between the subject groups. These observations indicate that evaluation of dysplastic nevi with the monoclonal antibody HMB-45, an apparent marker of proliferative or otherwise stimulated melanocytes, has no discriminating value for identifying subjects at increased historical risk for melanoma. The data, however, support the concept that so-called dysplasia within nevi, as defined by histologic criteria, actually represents the active or proliferative phase of melanocytic nevi.

Antibodies, Monoclonal↗

PubMed2005

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.

Back↗

PubMed1994

Effects of topical tretinoin on dysplastic nevi.

PURPOSE: As potential precursors of melanoma and markers of increased melanoma risk, dysplastic nevi are suitable targets of strategies for melanoma chemoprevention. We report the results of a pilot study of topical retinoic acid in patients with dysplastic nevi. PATIENTS AND METHODS: Five male patients with dysplastic nevi applied tretinoin to half of the back for 6 months. Baseline photographs of dysplastic nevi were compared with posttreatment photographs and assessed for morphologic change. At study completion, each subject had four nevi excised from the treated side and four from the untreated side of the back. Biopsies were histologically evaluated for the presence of dysplasia. RESULTS: All patients developed signs of irritation as a result of treatment. One patient was not compliant with treatment due to skin irritation. The four compliant patients showed significant decreases in the clinical atypia of treated lesions, with concomitant fading and even disappearance of many treated nevi. Histologically, only four of 16 treated nevi met histologic criteria for dysplasia, in comparison to 13 of 16 untreated nevi. CONCLUSION: These results suggest that there is concomitant clinical and histologic improvement in a significant percentage of dysplastic nevi treated with topical tretinoin. However, the utility of topical tretinoin for chemoprevention of melanoma is limited by difficulty of application and associated inflammation. While new strategies in chemoprevention of melanoma are explored, sun protection and assiduous avoidance of sunburn must remain the mainstay of melanoma prevention.

Administration, Topical↗

PubMed1990

Dysplastic nevi and malignant melanoma.

The incidence of melanoma has been steadily increasing, with a trend for this tumor to develop at younger ages. The only satisfactory treatment for melanoma is early intervention; therefore, routine screening for melanoma and dysplastic nevi during the general physical examination is important. The prevalence of dysplastic nevi is estimated to be 2 to 5 percent. Patients with dysplastic nevi appear to have at least a 6 percent lifetime risk of melanoma. In the most severely affected patients (those with a family history of dysplastic nevi and more than one melanoma), the lifetime risk may exceed 50 percent. Patients with dysplastic nevi merit periodic follow-up. Since these nevi tend to be familial, close relatives of affected patients may also benefit from a screening examination. Individuals at increased risk for melanoma may display one or more of the following risk factors: dysplastic nevi, freckling, tendency to sunburn and numerous common nevi. Such individuals may benefit most from education in sunburn avoidance, sunscreen use and self-examination for changing nevi. A better informed public and heightened physician awareness are the most effective means of reducing mortality from this virulent malignancy.

Diagnosis, Differential↗

PubMed1989

[Focal melanocytic atypia in dysplastic nevus cell nevi. Results of a serial section study].

Dysplastic nevi were diagnosed according to the ABCDE rule for recognition of early melanomas in 11 patients with familial dysplastic nevus syndrome (DNS) and in 39 patients with the sporadic variant of DNS. All these 50 patients exhibited multiple dysplastic nevi. On routine histological examination melanocytic atypia confirming the histological diagnosis of dysplastic nevus was found only in 12/50 cases. However, when cut consecutively dysplastic nevi with melanocytic atypia were diagnosed in 17 further cases (34%). In most cases (72.4%) only a mild degree of atypia (grade I) was found. Dysplastic nevi with severe melanocytic atypia (grades II-III) were found in all groups of sporadic and familial variants of DNS (with and without melanoma). To improve the prognostic value of the histological examination in dysplastic nevi significantly it must be of interest to add the degree of melanocytic atypia. With increasing degree of melanocytic atypia also the typical histological feature of dysplastic nevi become more significant. Since such atypia in dysplastic nevi is not necessarily sited in the centre of the lesion and since in most cases melanocytic atypia occurs focally, we believe that histological examination of dysplastic nevi must be undertaken by step section. Lesions suspected of being dysplastic nevi must be excised with margins of at least 2-5 mm for a correct histological diagnosis.

Adult↗

PubMed1989

[The number and distribution of nevus cell nevi in patients with malignant melanoma].

Total-body cutaneous examination of 211 patients with malignant melanoma (MM) and 157 controls showed that patients with MM had significantly more nevi. Among MM patients, men had more nevi on the trunk than women, and women had more nevi on the lower extremities than men. Men had an MM distribution that was similar to their nevus distribution. Women, however, had proportionately more MM on the legs and fewer MM on the neck. The "nevus density," defined as the number of nevi per unit surface area of skin, was higher in male MM patients. The nevus density was highest on the head and neck, and lower on the lower extremities and anterior trunk. Patients with nodular melanoma had more nevi than those with superficial spreading melanoma. MM patients with a family history of many nevi had more nevi than those without such a history. Patients with a family history of MM did not show an increased number of nevi, but they had larger numbers of suggestive nevi removed than those without a family history of MM. We believe that many of these observations are consistent with the view that MM is caused by a genetic predisposition to an overactive melanocytic system in combination with an external stimulant, such as UV radiation.

Adolescent↗

PubMed1988

Natural history of melanocytic nevi.

The natural history of common acquired nevi begins with junctional nevi, which first evolve into compound nevi and then intradermal nevi. The clinical appearance and histopathology of these lesions permit precise identification. Spitz nevi, blue nevi, congenital nevi and dysplastic nevi represent subcategories that also have easily identifiable features. An understanding of the nature of benign nevi makes it easier to identify potentially life-threatening melanomas.

Humans↗

PubMed1987

[Congenital nevus cell nevi of the skin--a nomenclatural and therapeutic problem].

The alarming increase in the incidence of malignant melanomas has caused interest to be focused on some of the precursors or tumor markers, such as dysplastic nevi or congenital nevocytic nevi. Both clinically and histologically, as well as by the incidence of malignancy, three groups of congenital nevocytic nevi may be distinguished. Small nevi (diameter less than 1.5 cm) are frequent, but it remains to be elucidated whether they involve an increased risk of malignancy. On the basis of differences in potential malignancy the larger congenital nevocytic nevi may be subdivided into two forms. Malignant melanomas occur more frequently and earlier in life in large nevi (diameter greater than 20 cm) compared with medium-sized nevi (diameter 1.5-20 cm). Medium-sized congenital nevi can usually be removed without considerable problems. In very large nevi, however, surgical treatment is more difficult. Since the risks involved in performing radical surgery in children may bear no relationship to possible benefits, repeated clinical examinations, detailed photographic documentation and immediate excision of any suspicious skin areas must be undertaken in such patients.

Humans↗

PubMed1985

Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects.

We examined 296 patients with a history of melanoma and 145 controls for the presence of atypical (dysplastic) nevi. We found that 34% of patients with melanoma and 7% of controls had clinically atypical (dysplastic) nevi. Patients and controls with atypical (dysplastic) nevi had more nevi than the subjects without. The number of nevi varies negatively and significantly with age (r = 0.37, P less than 0.001). Ten % of patients and controls had hypopigmented halos around one or more nevi. Both patients and comparison subjects with atypical (dysplastic) nevi tended to have this subtle variant of halo nevi more often than those without (r = 0.17, P less than 0.01). The number of nevi on the irides of melanoma patients was greater than that in the comparison group. The results of this study suggest that patients with a melanoma exhibit more commonly cutaneous and ocular pigmentary lesions than comparison subjects without a melanoma.

Adolescent↗

PubMed2001

Spitz nevi display allelic deletions.

BACKGROUND: Spitz nevi are acquired benign melanocytic lesions that occur in childhood and adolescence. Histologically, they resemble malignant melanoma and were first termed benign juvenile melanoma. Several studies have attempted the difficult task of establishing diagnostic criteria to differentiate between Spitz nevi and malignant melanoma. OBJECTIVE: To elucidate sets of diagnostic criteria for differentiation between the 2 lesions. DESIGN: We aimed to search for allelic deletions in Spitz nevi and to evaluate whether loss of heterozygosity (LOH) or microsatellite instability (MSI) would be a valuable diagnostic tool to differentiate between Spitz nevi and malignant melanoma. SETTING: Two areas within each of 5 lesions were microdissected, and LOH and MSI were evaluated at chromosomes 6q (using polymorphic DNA marker D6S305), 9p21 (D9S171, IFNA, D9S265, and D9S270), 10q (D10S185), and 14q (D14S53). PATIENTS: Five Swiss patients with Spitz nevi. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Allelic deletions may serve as a diagnostic tool to distinguish Spitz nevi from melanoma. RESULTS: All lesions were informative, displaying LOH or MSI with at least one marker. No LOHs were found at 14q. At 6q, MSI was found in 2 dissected areas from the same lesion; the remaining lesions were noninformative. Loss of heterozygosity was found in 2 of 6 areas at D9S171, 2 of 6 at IFNA, 3 of 6 at D9S270, 3 of 4 at D9S265, and 1 of 4 at D10S185. Microsatellite instability was found in 1 of 4 areas at D9S265. CONCLUSIONS: With the markers used in our study, Spitz nevi display LOH and MSI similar to those in melanoma. Analysis of LOH or MSI is therefore not a suitable diagnostic tool in distinguishing Spitz nevi from melanoma.

Adolescent↗

PubMed2003

Analysis of heterogeneity of atypia within melanocytic nevi.

BACKGROUND: Incisional biopsy of clinically atypical nevi continues to be a common practice. Questions can arise as to the adequacy of these partial biopsies. OBJECTIVE: To determine whether incisional (partial) biopsy specimens may be considered representative of the entire lesion, atypical nevi submitted to our dermatopathology laboratory were examined for the presence or absence of heterogeneity of atypia within the individual nevi. DESIGN: The study included 250 histologically atypical nevi that were selected consecutively from pigmented lesions that were submitted to our dermatopathology laboratory by community and academic dermatologists for histopathologic analysis. Also, 23 moderately to severely atypical and 25 severely atypical nevi from consecutive submissions were added for statistical reasons. Lesions with both clear and involved margins were used. Lesions were considered homogeneous if the atypia involved the entire lesion or heterogeneous if either the atypia was focal or if different degrees of atypia occurred within the same lesion. Atypia was defined by the usual parameters of architectural and cytologic atypia and host response. Also, the degree of atypia in relationship to heterogeneity and to patient age was determined. SETTING: The Dermatopathology Laboratory, University of California, Irvine. MAIN OUTCOME MEASURES: Outcome measures included the percentage of nevi exhibiting heterogeneity of atypia, heterogeneity of atypia in relation to patient age, degree of atypia in relation to patient age, and degree of atypia in relation to the presence of heterogeneity of atypia. RESULTS: Of the 298 nevi examined, 107 (35.9%) were heterogeneous in atypia and 191 (64.1%) were homogeneous in atypia. There was no significant difference in age between patients with heterogeneous lesions and those with homogeneous lesions. There was a statistically significant correlation between the degree of atypia and patient age. The average age of patients with a lesser degree of atypia was 36.9 years, while the average age of patients with a greater degree of atypia was 44.8 years (P<.005). There was no significant correlation between degree of atypia and heterogeneity of atypia (correlation coefficient, 0.1). CONCLUSIONS: A clinically significant proportion of atypical nevi exhibited heterogeneity of atypia. Also, there was a significant relationship between the degree of atypia and increasing age (P<.005). Therefore, if a clinically atypical nevus warrants a biopsy, these results give additional support for complete excisional biopsy (which can include shave or punch) to assure adequate histopathologic sampling of the lesion.

Adult↗

PubMed2006

Wilms tumor 1 expression present in most melanomas but nearly absent in nevi.

BACKGROUND: Pigmented lesions are common, yet they present diagnostic and therapeutic challenges. They range from nevi, which are clinically stable, to melanomas, which are notorious for distant metastasis and death. Both nevi and melanomas arise from melanocytes, which are neural crest derivatives, and melanocyte precursors migrate from the paraspinal area to their eventual location at the dermoepidermal junction. Atypical nevi have been clinically considered to be precursors of melanoma, and recently, biochemical abnormalities have been found that are present in both nevi and melanomas, including inactivation of the p16INK4a tumor suppressor gene and mutations in B-raf. These mutations suggest not only that nevi and melanomas share a common origin but also that additional events are required for transformation to malignant melanoma. OBSERVATIONS: We performed a Panomics protein array comparing a radial growth melanoma cell line with a vertical growth melanoma cell line and found that the transcription factor Wilms tumor 1 is highly expressed in the vertical growth cell line compared with the radial growth cell line. Using immunohistochemical analysis, we compared expression of archival nevi and melanomas in a tissue microarray. CONCLUSION: We found that Wilms tumor 1 is expressed in most melanomas but is nearly absent in nevi. Immunohistochemical analysis for Wilms tumor 1 may be clinically useful in distinguishing nevi from melanoma.

Biomarkers, Tumor↗

PubMed1998

Choroidal nevi in a white population: the Blue Mountains Eye Study.

OBJECTIVE: To determine the prevalence, morphologic characteristics, associations, and frequency of features reported to predict growth of choroidal nevi in a large population-based sample. METHODS: A total of 3654 subjects aged 49 to 97 years participating in the Blue Mountains Eye Study had a detailed eye examination, including photography of 6 standard retinal fields. Nevi were graded from photographs. RESULTS: Nevi were present in 6.5% of the population (n = 232), and were distributed equally between eyes. There was a slight decrease in nevus prevalence with increasing age. Nevus prevalence was higher in women than men, but this difference was not statistically significant. The mean nevus diameter was 1.25 mm (SD, 0.72 mm; range, 0.5 to >4.5 mm). Eighty-seven percent of nevi were blue gray and 6% had a hypomelanotic or amelanotic appearance. There were no significant associations between nevi and iris or skin color or sun-induced skin damage, but nevi were significantly less frequent in persons with blond hair. No nevus associations were found with visual impairment, cataract, or glaucoma. Clearly visible drusen were seen on 42% of nevi and were larger and more centrally distributed as nevus size increased. Features previously identified as predicting nevus growth, such as serous elevation and orange or other pigment, were seen rarely. CONCLUSION: Choroidal nevi in the general population are frequent, small, have few features that are commonly reported to indicate potential for growth, and rarely affect visual acuity.

Age Distribution↗

PubMed1996

Number and distribution of melanocytic nevi in individuals with a history of childhood leukemia.

BACKGROUND: An increased number of melanocytic nevi at the termination of chemotherapy has been documented in children with hematologic malignancies. The persistence of the increased number of nevi over time and the relationship with personal (e.g. phenotype) and disease related variables remain to be explored. METHODS: One hundred Italian patients diagnosed as having acute lymphatic or myeloid leukemia, after 1975, were recruited and compared with a group of 100 control individuals drawn from friend of the enrolled patients. Information regarding lifetime sun exposure, phenotypic characteristics, and number of nevi was collected by experienced dermatologists. Counts of nevi were expressed both as totals and as counts per unit of body surface area ("density"). Multiple linear regression analysis was employed to control for potentially confounding factors when comparing patients and controls. RESULTS: The patients and controls were fairly comparable in terms of constitutional characteristics, but the patients had a significantly higher number and density of nevi > or = 2 mm or larger in diameter. In addition, patients had a greater number of large nevi ( > or = 6 mm in greatest dimension), and of nevi in unusual areas, such as the palms and soles. Differences in nevus density between patients and controls were notably maintained in the older age group ( > 12 years). None of the disease-related factors analyzed (e.g. treatment protocol and radiotherapy), appeared to be significantly correlated with nevus density. CONCLUSIONS: Patients with a history of childhood leukemia have a sustained increase in their nevus density. A fairly convincing body of evidence indicates that a large number of melanocytic nevi is the strongest risk factor for melanoma. Therefore, the utility of periodic skin examination of these should be considered.

Acute Disease↗

PubMed1980

Pigmented nevi of the oral mucosa: a clinicopathologic study of 32 new cases and review of 75 cases from the literature. Part II. Analysis of 107 cases.

Review and analysis of data of seventy-five cases from the literature, together with an additional thirty-two new cases, revealed that nevi of the oral mucosa are not rare and may be more common than previously thought. Nevi of the intramucosal type are the most common, followed by the common blue nevus. Compound nevi are uncommon, and junctional nevi are very rare. The data are analyzed as to the location, presence of clinical pigmentation, configuration, size, and duration of the nevi, as well as the patient's age, sex, and race. Oral nevi (especially those that are clinically nonpigmented) are often misdiagnosed, indicating that they are far more common than they would seem from the reported cases. The potential for oral nevi to undergo malignant transformation is unclear because of the paucity of cases and limited follow-up. Nevertheless, we recommend that all oral pigmented nevi be removed.

Adolescent↗

PubMed2005

Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma.

Protease-activated receptors (PARs) are members of the G protein-coupled receptor superfamily that are activated by the proteolytic cleavage of their amino terminal domain. PAR-1 activation by thrombin results in several biologic effects, including platelet adhesion to other cells or extracellular matrix, fibroblast, and endothelial cell growth, whereas PAR-2, activated by trypsin, has mainly a proinflammmatory and angiogenetic role. PAR-1 and PAR-2 modulate cell proliferation in physiopathologic cell invasion processes, suggesting that they may play a role in the setting of cancer growth and metastasis. Here, we have investigated the expression of PAR-1 and PAR-2 proteins by immunohistochemistry in a series of benign and malignant melanocytic lesions: 20 melanocytic lesions (10 common melanocytic nevi and 10 atypical or "dysplastic" melanocytic nevi) and 50 melanomas (10 in situ melanomas, 10 melanomas T1, 10 melanomas T2, 10 melanomas T3 to T4, and 10 metastatic melanomas). PAR-1 was significantly overexpressed in atypical nevi and melanomas in comparison with common melanocytic nevi. PAR-2 was strongly and diffusely expressed by immunohistochemistry in all melanocytic lesions, with no statistically significant differences between nevi and melanomas. Because we found a differential expression in PAR-1 protein, but not in PAR-2, we next investigated the expression of PAR-1 messenger RNA (mRNA) by ribonuclease protection assay in paraffin-embedded tissues using a paraffin block RNA isolation procedure. Similarly to immunohistochemical results, PAR-1 mRNA expression was significantly higher in atypical nevi and melanomas in comparison with common nevi and controls. Overexpression of PAR-1 in atypical nevi and melanomas supports a role for PAR-1 in the initial phases of melanoma development as well as in tumor progression and metastasis. Conversely, the significance of PAR-2 up-regulation in both benign and malignant melanocytic lesions requires further research.

Adult↗

PubMed2004

Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway.

Spitz nevi are benign melanocytic nevi that overlap histopathologically with melanoma. We previously found copy number increases of chromosome 11p frequently paralleled by mutations in the HRAS oncogene mapping to this region. In this study, we explored mechanisms that inhibit proliferation in the presence of HRAS activation. We analyzed MAP-kinase activation using immunohistochemistry for phospho-ERK, cyclin D1, and microphthalmia transcription factor expression in 17 Spitz nevi with and 18 Spitz nevi without 11p copy number increase. We found relatively high levels of phospho-ERK and cyclin D1 expression suggesting MAP-kinase pathway activation in both groups of Spitz nevi. However, Spitz nevi with 11p copy number increases showed significantly higher levels of cyclin D1 expression and lower levels of microphthalmia transcription factor expression suggesting stronger MAP-kinase pathway activation in this group. Contrasting this apparent activation, the proliferation rate as assessed by Mib1 expression was low in both groups. An analysis of cell-cycle inhibitory proteins including p16, p21, and p27 showed that the majority of Spitz nevus cells expressed high levels of p16, with cells of the cases that had increased copy number of 11p expressing significantly higher levels than those of Spitz nevi with normal copy number of 11p. We propose that in benign nevi with constitutive activation of the MAP-kinase pathway, p16 functions as an essential mediator of oncogene-induced senescence preventing progression to melanoma.

Calibration↗

PubMed1992

Giant pigmented nevi: clinical, histopathologic, and therapeutic considerations.

Eighty pediatric patients with giant pigmented nevi more than 20 cm in their greatest diameter are reported. The incidence was 1 in 4150 general pediatric outpatients. The mode of inheritance of giant pigmented nevi is probably multifactorial; four second-degree relatives of our patients also had large nevi, and there was a 2:1 female predominance. Satellite nevi were present in 74% and nevi in mucous membranes in 31% of the patients. Eighty-six percent of nevi were pigmented and hairy. Benign nodules were observed in 19% of the patients and plexiform overgrowths in 6%. Nevi extensively involving the extremities resulted in reduced growth of the affected limb. Electroencephalograms showed abnormalities in 20% of the patients with giant pigmented nevi involving the head and upper portion of the trunk. Malignant transformation appeared in four patients and was fatal in three of them. Management consisted of observation only in 49%, surgery in 27.5%, chemical peel in 21%, and dermabrasion in 2.5% of the patients. The mean follow-up was 4.7 years.

Follow-Up Studies↗