Congenital-nevus-like nevi, nevi spili, and café-au-lait spots in patients with malignant melanoma

The prevalence of congenital-nevus-like nevi (CNLN) in a group of 105 adults who had malignant melanoma (MM) was compared with that in a control group of 601 adults not afflicted by MM. Total cutaneous examinations were performed on both groups. The control group presented with complaints other than pigmented lesions. In this series, 10 (9.5%) of the group with MM had clinically diagnosed CNLN 1.5 cm or larger in diameter. These CNLN were not in contiguity with the MM sites. The 9.5% prevalence of CNLN in the group with MM was significantly higher (p less than 0.005) than the 2.5% CNLN observed in the control population. None of the patients in either group had large congenital nevocytic nevi (greater than or equal to 20 cm). In addition, in the group with MM, 5 patients (4.8%) had nevi spili (NS) and 13 (12.4%) had café-au-lait spots (CLS). The prevalence rates for these two types of pigmented lesions were not significantly different from those observed in the nonmelanoma control group (2.3% for NS; 13.8% for CLS). The relative risk for developing MM is 4.1 in people with CNLN compared with those without CNLN, which indicates that these nevi may be markers for individuals prone to develop malignant melanoma.     

Absence of BRAF gene mutations differentiates spitz nevi from malignant melanoma

BACKGROUND: Distinction of Spitz nevus from malignant melanoma is sometimes difficult on the basis of conventional histology. A high rate of BRAF gene mutations in malignant melanomas (66%) and nevi (82%) has recently been reported. MATERIALS AND METHODS: We screened a series of 20 Spitz nevi for BRAF mutations in exons 11 and 15 by denaturing gradient gel electrophoresis (DGGE). RESULTS: BRAF mutations could not be identified in Spitz nevi. CONCLUSION: Our results show that mutations within the BRAF gene are useful markers for the differential diagnosis between Spitz nevus and malignant melanoma.     

Iatrogenic effects of general anesthesia in children: considerations in treating large congenital nevocytic nevi

Dermatologists are often faced with the decision of when to operate on a child at risk for developing malignant melanoma in a large congenital nevocytic nevus. As a series of operations is usually required, an understanding of the lethal and nonlethal effects of the general anesthesia is necessary. This paper discusses these potential iatrogenic effects on the child's physical and psychological development. Suggestions are given for optimal times to operate, considering both psychological and physical factors, (i.e., 6-9 months or 8-12 years of age) and ways to minimize unwanted side effects.     

YAP在黑素瘤和痣细胞痣中的表达及意义

目的:研究YAP在皮肤黑素瘤及痣细胞痣中的表达变化情况。方法:采用免疫组化方法检测20例正常皮肤组织、28例痣细胞痣和32例黑素瘤皮损中YAP的表达。结果:在正常皮肤组织中,YAP弱表达于表皮基底层,在表皮全层所占阳性率为25.00%。在痣细胞痣中,YAP表达于靠近表皮的部分痣细胞中,阳性率为32.14%。在黑素瘤中,可见YAP高表达于几乎所有的瘤细胞中,阳性率为93.75%。YAP在黑素瘤中的表达显著高于正常皮肤组织和痣细胞痣(P＜0.001)。而在痣细胞痣中的表达与正常皮肤组织无显著差异(P＞0.05)。结论:YAP可能参与黑素瘤和痣细胞痣的发生和发展。     

Clinical recognition of early forms of malignant melanoma

The clinical diagnosis of malignant melanoma (MM) is based on the subjective evaluation of objective measurable parameters (criteria). The accuracy of melanoma diagnosis by dermatologists is only 75%. Particularly difficult is the diagnosis of precursors or early stages of MM. Therefore, we have studied on the one hand the intra- and interindividual reproducibility of the clinical diagnosis of pigmented lesions, and on the other hand the clinico-histopathological correlation. In addition, we have conducted a preliminary investigation designed to evaluate whether image analysis (objective and reproducible) could be used as an auxiliary instrument to differentiate between benign and malignant melanocytic lesions. In the clinical study, the intraindividual reproducibility of the combination of criteria was 69%. The interindividual reproducibility of single criteria even exhibited a range of up to 36%. Histologically "atypical/dysplastic" melanocytic lesions were considered to require excision as frequently as histologically regular melanocytic lesions. Using image analysis (single threshold segmentation, standard deviation of intensity distribution, ratio of area to circumference, Fourier analysis), we could show that it may be possible to differentiate between benign and malignant melanocytic lesions. Therefore, image analysis may be very helpful in determining the dignity of melanocytic lesions.     

Dysplastic nevi in association with multiple primary melanoma

Risk factors for multiple primary cutaneous melanoma were evaluated in a case-control study. Eight cases of multiple primary melanoma were matched on sex, age, and education to 24 first primary melanoma controls. Risk factors examined in the analysis included pigmentary characteristics, history of sun exposure, and nevi. The importance of histologically dysplastic nevi (DN) and clinically atypical nevi was of particular interest. Single-factor conditional logistic regression analysis showed that first primary melanoma patients with histological DN are at increased risk for a second primary (odds ratio, 6.2; 95% confidence interval, 1.2-33.4). Patients with two or more clinically atypical nevi also have elevated risk for a second primary (odds ratio, 8.8; 95% confidence interval, 1.0-80.7). Two-factor logistic models were used to evaluate the effect of histological DN while controlling singly for all other variables as potential confounders. Odds ratios for the association of histological DN varied from 6.1 to 10.4 when adjusting singly for pigmentary and sun exposure variables. In the two-factor model that included histological and clinical DN, both variables retained marginally significant statistical association with multiple primary melanoma. These results suggest that DN is a marker of increased risk for multiple primary melanoma and suggest that melanoma patients with evidence of DN should be followed closely for the development of additional primaries.     

Association of microvessel density with infiltrating cells in human cutaneous malignant melanoma

Vascularization and host response to malignant tumors may have common molecular regulators, therefore, we analyzed the relationship between microvessel density (MVD) and tumor infiltrating cells in cutaneous malignant melanoma. Density of lymphocyte subpopulations, macrophages, dendritic cells and CD34⁺ microvessels was determined by immunohistochemistry in primary tumor samples from fifty-two patients with melanoma thicker than 1 mm. Intratumoral MVD did not show significant association with infiltration for any of these cell types. In the case of peritumoral reactive cell densities analyzed in the whole patient population, a positive correlation of MVD was found with CD3⁺ T cell density. This association was stronger in melanomas >4.0 mm and in visceral metastatic tumors. In these subgroups similar phenomenon was observed for CD8⁺ cells. We found significant correlation of MVD with CD68⁺ macrophage density only in the highest thickness category, and weak associations with B-cell and dendritic cell infiltration in visceral metastatic cases. MVD did not vary significantly in tumors categorized according to thickness, localization, ulceration or histological type. However, both intratumoral MVD and macrophage infiltration were significantly higher in male patients compared to females. The correlation of immune cell density with tumor vascularization and gender differences in vascularity and macrophage infiltration of melanoma deserve further attention.     

Association of MMP8 gene variation with an increased risk of malignant melanoma

Matrix metalloproteinases (MMPs) are implicated in the development of cancers including malignant melanoma (MM) and breast cancer. We tested the possible association of MMP1 and MMP8 gene variation with these two types of cancer. We genotyped 300 unselected patients with MM, 300 consecutive breast cancer cases, 300 controls for melanoma, and 300 controls for breast cancer (age-matched and sex-matched healthy adults with negative cancer family histories). Our study showed that the MMP8 gene rs11225395 polymorphism was associated with the risk of developing MM (odds ratio: 1.69; 95% confidence interval: 1.02-2.80; P=0.040) for the A/A genotype and 1.49 (95% confidence interval: 1.03-2.17; P=0.035) for the A/G genotype compared with the G/G genotype. The A allele was over-represented among MM cases compared with controls (odds ratio=1.54; P=0.017). In-vitro assays showed that the A allele had a higher promoter activity than the G allele in melanoma cells. No association was detected between this variant and breast cancer susceptibility. We found no strong association between MMP1 variation and the risk of MM or breast cancer. The finding of this study indicates an influence of MMP8 gene variation on melanoma susceptibility.     

Significance of DNA abnormalities in primary malignant melanoma and nevi, a retrospective flow cytometric study

DNA ploidy of melanocytic skin tumors from 87 patients (53 primary melanomas, 34 nevi) was determined by flow cytometry from routinely prepared paraffin blocks. Ploidy data correlated strongly with conventional morphological parameters. Only 1 of 34 nevi, but 13 of 53 melanomas were aneuploid. Among the melanomas, none of 21 levels I-III melanomas was aneuploid, but 13 of 32 levels IV and V melanomas were aneuploid. There was also a significant correlation between increasing Breslow thickness and the presence of DNA aneuploidy. For 33 melanoma patients with over 2 yr of follow-up (average, 7.1 yr), only 4 of 23 diploid tumors have recurred, but 9 of 10 aneuploid tumors have recurred. We conclude that the biological potential of melanocytic skin tumors is strongly linked to DNA aneuploidy. Since this parameter can be conveniently determined from paraffin blocks, determination of ploidy abnormalities in these tumors may be clinically useful.     

Plantar malignant melanoma -- a challenge for early recognition

The incidence of malignant melanoma has been continuously increasing over the last few decades. Non-plantar melanomas are nowadays usually diagnosed and treated surgically at an early stage. In contrast, melanoma in a plantar location is usually diagnosed at an advanced tumour stage, conferring a poor prognosis. To discover the reasons for this remarkable difference in recognition and prognosis, we analysed our cases of plantar malignant melanoma in a retrospective study. From 1990 to 1997, we treated 925 melanoma patients. Of these, 68 cases (7%) were classified as plantar melanoma. For non-plantar melanoma patients the mean age was 52.6 years, the mean Clark level was 2.8 and the mean tumour depth was 1.22 mm. In contrast, the mean age of patients with plantar melanoma was 63.3 years, the mean Clark level was 3.61 and the mean tumour depth was 2.55 mm. The mean time between the first observation of the plantar skin lesion and the first consultation with a physician (patients' delay) was 4.8 years and, on average, it took an additional 7 months before adequate surgical treatment was performed (physicians' delay). The prognosis of our patients was poor. In 98.5% (n = 67) further metastases were observed on follow-up. Since there is still no cure for advanced plantar malignant melanoma, the early detection and subsequent surgical treatment of plantar melanoma is decisive for the prognosis. Based on our results, the poor survival can be improved by a significant reduction in the time period between the first observation of a plantar skin lesion and surgical treatment. Therefore there is an urgent need for special preventive health care campaigns to reduce significantly both the patients' and the physicians' delay.     

DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.

BACKGROUND: Exposure to UV radiation is associated with cutaneous malignant melanoma (CMM). In mammalian cells, UV radiation induces DNA damage that can be repaired by the nucleotide excision repair system. We designed this case-control study to determine whether DNA repair capacity (DRC) is associated with the risk of CMM and to identify risk factors that may interact biologically with DRC in the development of melanoma. METHODS: Global DRC was measured in lymphocytes with the host-cell reactivation assay. Data were analyzed by use of multiple regression models. All statistical tests were two-sided. RESULTS: DRC could be determined for 132 case patients with incident melanoma and for 145 age- and sex-matched control subjects. No statistically significant association between melanoma risk and DRC by itself was found (odds ratio [OR] = 1.0; 95% confidence interval [CI] = 0.6 to 1.7, adjusted for age, sex, lymphocyte viability, and sample storage time). DRC, however, strongly influenced CMM risk in individuals with a low tanning ability or dysplastic nevi. Individuals with a low tanning ability and a low DRC had a higher risk for CMM (OR = 8.6; 95% CI = 2.7 to 27.5) than individuals with a higher tanning ability and a high DRC. Likewise, individuals with dysplastic nevi and a low DRC had a higher relative risk (OR = 6.7; 95% CI = 2.4 to 18.6) than those lacking dysplastic nevi and having a high DRC. Subjects with dysplastic nevi and a high DRC had an intermediate risk. A likelihood-ratio test gave statistically significant interactions between DRC and tanning response (P =.001) and between DRC and dysplastic nevus status (P =.04), which were independently associated with CMM risk. CONCLUSIONS: DRC may modify the risk for melanoma in the presence of other strong risk factors, such as a low tanning ability and the presence of dysplastic nevi. The occurrence of melanoma in subjects without these risk factors appears to be independent of DRC.     

Clinical and histopathologic characteristics of early lesions of subungual malignant melanoma

Twenty-one Japanese cases of subungual malignant melanoma were investigated clinically and histologically. In the majority of the cases, the initial sign of the disease was confirmed to be melanonychia striata. Five cases of Clark's Level I melanoma were found in the series. Melanonychia striata had appeared as the initial sign in these five cases. Melanonychia striata is frequently observed in persons who are not white and is attributed to various local and systemic causes. Detailed clinical analysis of the five cases of early subungual melanoma showed that melanonychia striata with the following characteristics may increase the risk of early subungual melanoma developing: it is noticed during adulthood, it is broader than 6 mm, it is brownish with variegated shades or homogenously black, and it is accompanied by periungual pigmentation (Hutchinson's sign). Detection of early lesions of subungual melanoma is beneficial not only for the improvement of prognosis, but also for the preservation of the affected phalanx.     

Correlation of clinical pigmentary characteristics with histopathologically-confirmed dysplastic nevi in nonfamilial melanoma patients. Studies of melanocytic nevi IX

The dysplastic melanocytic nevus (DMN) is the key clinical marker for the familial dysplastic nevus syndrome and has also been associated with high risk for non-familial melanoma. Characterisations of DMN itself have been qualitative and on a case-by-case basis. In this study, we provided clinical and histological characterisations for each of 150 pigmented lesions from 150 patients with prior malignant melanoma. The steps involved in the study were as follows: (1) The two to four clinicians characterised pigmented lesions on each of 150 patients, and the lesion closest in characteristics to an atypical nevus was quantitatively described based on size, border characteristics and colour characteristics; (2) The lesion was then removed and independently quantified by a single dermatopathologist without knowledge of the clinical features; (3) We computed the correlation between each of the clinical variables and each of the histologic features for each of the 150 patients. Histologic diagnosis of dysplastic nevus was strongly associated with total number of palpable arm nevi, total number of any arm nevi, total number of nevi on the body of any type, and total number of clinically atypical nevi on the body (correlation coefficients 23.2% to 30.4% with P less than 0.01 in each instance). There were also strong correlations between the counts of numbers of nevi and certain types of architectural histologic features, including fusion (bridging of junctional nests), lymphocyte response and fibroplasia of the papillary dermis. Histologic evaluation of solar elastosis was negatively correlated with total numbers of nevi and total number of clinically atypical nevi (P less than 0.01). Freckling on forearm and on shoulders showed no significant positive or negative correlations with any of the histologic features nor with overall diagnosis of dysplastic nevus. We conclude that observations regarding total numbers of nevi (either normal or clinically atypical nevi) are correlated with nuclear and architectural histologic dysplasia on biopsy of the most atypical pigmented lesions.     

Inter-clinician agreement on the recognition of clinical pigmentary characteristics of patients with cutaneous malignant melanoma. Studies of melanocytic nevi, VI

The number and type of melanocytic nevi are among the most important known predictors of risk for cutaneous malignant melanoma. In this study, examinations of the skin were conducted by two to four clinicians on 153 patients with newly diagnosed melanoma, and the agreement among clinicians was quantified regarding number of nevi and freckling. The index of agreement (calculated as the intra-class correlation coefficient) was 59.7% and 69.0% for freckling on the right forearm and on the shoulders, respectively; agreement was above 50% for only one of six pairs of clinicians in examining freckling on the right forearm, while agreement was above 50% for four of the six pairs of clinicians in examination of freckling on the shoulder. For palpable nevi of the arms (used in at least two case-control studies as a predictor of risk), the agreement was 36.1% when computed for three examiners assessing 81 patients. However, for total arm nevi (both palpable and non-palpable), assessed on a subset of 48 patients, the agreement was 88.2%; this and other analyses indicated that the difficulty in achieving a consensus for palpable nevi lay in whether or not lesions were considered to be 'palpable' or 'non-palpable'. Agreement for total number of atypical nevi on the body and total number of all types of nevi were 87.4% and 91.8% respectively. These data suggest that the kinds of lesions on which agreement might be reached are total atypical nevi and total nevi of all types on the arms and on the entire body. Greater difficulty might be found in achieving consistency among investigators and among clinicians in examining individual patients with respect to freckling on the arms and 'palpable' nevi. However, some consistency was achieved even with these latter two clinical features.