Histopathologic spectrum of clinically atypical melanocytic nevi. II. Studies of nonfamilial melanoma

We studied the clinically most atypical pigmented lesion removed from each of 142 patients with newly diagnosed sporadic melanoma. The specimens were categorized as to the type of nevus, ie, junctional or compound, presence of congenital features, and degree of nuclear atypicality--presence of nuclear enlargement, nuclear pleomorphism, hyperchromatism, and prominent nucleoli--of intraepidermal nevomelanocytes. The frequency of nuclear abnormality was graded as 1 (rare cells), 2 (10% to 50% of cells), or 3 (greater than 50% of cells) for each nuclear parameter. Among all lesions, 42 (29.6%) were junctional nevi, 74 (52.1%) were compound nevi, and 14 (9.9%) were dermal nevi. Eighteen percent of the total were either dysplastic nevi (23 cases) or malignant melanoma in situ (three cases). Fourteen nevi (9.9%) had congenital features. There were 12 junctional and 39 compound nevi and one dermal nevus that exhibited nuclear abnormality, but only four junctional nevi compared with 19 compound nevi had sufficient atypia for a designation of dysplastic nevus. Only two nevi with congenital features demonstrated any nuclear abnormality, and these were clearly nondysplastic. Thus, among nevi surgically removed as the clinically most atypical lesion in this study, compound nevi were much more likely to demonstrate nuclear atypia (and dysplasia) than were other nevi, ie, junctional or dermal nevi, or nevi with congenital features.     

Comparison between familial and sporadic cutaneous melanoma in Valencia, Spain

Some clinical, pathological and genetic features have been associated to familial melanoma, particularly multiple melanoma and earlier age at diagnosis.
To compare the clinical, epidemiological and pathological differences between familial and sporadic melanoma patients in Valencia, Spain, a series of 959 patients with cutaneous melanoma were selected at a single institution. For this study the following variables were selected: age, sex, melanoma site and presence of solar lentigines on the melanoma surrounding skin, histological subtype, tumor thickness, stage, family and personal history of cutaneous melanoma and of other neoplasias, personal history of non-melanoma skin cancer, past personal history of severe sunburns, cutaneous phenotype (phototype, hair and eyes colors number of common nevus, number of atypical nevi, presence of solar lentigines).
Forty-one (4.28%) familial and 918 sporadic melanoma were identified. Among the multiple variables studied, a younger age at diagnosis (median age of 42 vs 53 years), higher frequency of the presence of at least one clinically atypical nevus (36.1% vs 17.7%), multiple melanomas (12.2% vs 3.4%) and red/blonde hair (33.3% vs 18.9%), and a lower rate of cases with solar lentigines in melanoma site (33.3% vs 56.3%) were found for familial cases. Except for hair color and age, the other variables remained statistically significant after the multivariate study. Interestingly, no acral melanomas were found among the familial cases.
In summary, phenotypic risk factors for familial melanoma are a tendency to develop multiple melanomas, to have clinically atypical nevi and to present less actinic damage at the melanoma site. All these results enhance the relevancy of genetic susceptibility associated to the ability to produce atypical nevi and partly to a higher sensitivity to the sun.     

Dysplastic nevi as risk markers of sporadic (nonfamilial) melanoma. A case-control study

The melanoma risk associated with dysplastic nevi outside the context of familial melanoma was studied by the case-control method. One hundred five newly diagnosed incident melanoma cases with negative family histories for familial melanoma and 181 controls (frequency matched for race, age, and sex) were studied by personal interview and cutaneous examination. The prevalence of dysplastic nevi was 41 (39%) of 105 in the cases and 13 (7%) of 181 in the controls. The odds ratio for dysplastic nevi by multiple logistic regression analysis simultaneously correcting for age, sex, eye color, hair color, actinic damage, freckles, and total number of nondysplastic nevi was 6.8 (95% confidence interval, 2.7, 16.9). This study supports the significance of dysplastic nevi as markers of increased risk for nonfamilial melanoma.     

Genetics of familial and sporadic melanoma

Like many other cancers, melanoma has a significant genetic basis. However, its genetic pathways may involve multiple genes with probable interactions with sun exposure. Germline mutations in p16 or CDKN2A are found in a significant percentage of relatively rare melanoma families but p16 mutations are uncommon in sporadic tumours. p16 may still be involved by other mechanisms of inactivation; however, it is clear that other melanoma genes remain to be discovered. Family, case-control, twin and sib-pair analyses as well as DNA chip technology may shed some light on genes involved in melanocytic differentiation and skin pigmentation. Recent public health campaigns have not been very successful in changing behaviour regarding tanning, and the relationship between sun exposure and melanoma is very complex. With the understanding of genetic alterations leading to this tumour, follow-up strategies and behavioural interventions may be more specifically designed to target high risk groups.     

HLA in familial malignant melanoma

In a family displaying the familial atypical multiple-mole melanoma syndrome, linkage analyses were performed between HLA and an assumed dominant gene respectively determining each of the following affected phenotypes: precursor lesions; cutaneous malignant melanoma (CMM); and precursor lesions or CMM or both. The results suggest that there is a complex mechanism involving several factors, genetic and environmental interacting with the gene determining precursor lesions to cause the neoplastic transformation.     

Dysplastic nevus in histologic contiguity with acquired nonfamilial melanoma. Clinicopathologic experience in a 100-bed hospital

In the face of alarming rates of increase in melanoma worldwide, dysplastic nevi, especially any that are clinically changing in size, color, or borders, may be regarded as playing a potential role in the progression to a tumor stage. Dysplastic nevi are known to occur in multiples in family members of heritable malignant melanoma. Intraepidermal atypical melanocytes fulfilling the criteria of the dysplastic nevus were seen in histologic contiguity with superficial malignant nonfamilial melanomas in six of 13 patients. With one exception, all melanomas in this study that were associated with histologically contiguous dysplastic nevi were relatively thin, allowing identification of the melanoma at a potentially curable stage.     

Pancreatic carcinoma surveillance in patients with familial melanoma

OBJECTIVE: To determine the optimal methods for pancreatic adenocarcinoma surveillance in high-risk patients with familial melanoma and cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. DESIGN: Case report with pedigree analysis and literature review, with an emphasis on guideline development for high-risk kindreds with familial pancreatic adenocarcinoma. SETTING: A university-affiliated familial melanoma research clinic.Patients The proband was referred as a participant in a research clinic protocol and was found to carry a germline CDKN2A mutation and have a history of melanoma and pancreatic adenocarcinoma. A total of 179 family members were identified through the Utah Population Database and underwent evaluation for history of melanoma and pancreatic adenocarcinoma.Intervention/ METHODS: Comprehensive family history and pedigree analysis performed by means of personal interview, medical record review, and use of cancer registry and population database records. Mutation status was confirmed by results of DNA sequence analysis. Tumor identity was confirmed with immunohistochemical markers. MAIN OUTCOME MEASURES: Estimated risk for pancreatic adenocarcinoma in a high-risk family with CDKN2A-positive melanoma. Guidelines for surveillance in these families were based on review of the literature. RESULTS: Sequence analysis confirmed a CDKN2A mutation, and immunohistochemical evaluation confirmed the diagnoses of metastatic melanoma and metastatic pancreatic adenocarcinoma. Pedigree analysis showed an observed-expected ratio of 8.9 to 12.6 for pancreatic adenocarcinoma and 16.4 to 20.8 for melanoma in this family. Guidelines used for surveillance of kindreds at high risk for pancreatic adenocarcinoma were applied to families with CDKN2A melanoma.Conclusion Patients with melanoma and a germline CDKN2A mutation should be considered for pancreatic adenocarcinoma surveillance that is based on the most recent published studies.     

Increased incidence of multiple melanoma in sporadic and familial dysplastic nevus cell syndrome

In 280 melanoma patients all data concerning familial and personal history, histology, and therapy were verified. All patients underwent total-body skin examination to check for the presence of dysplastic nevus syndrome (DNS). In 257/280 patients (91.8%) solitary melanomas were found, while in 23/280 patients (8.2%) multiple melanomas occurring simultaneously or consecutively were ascertained. Surprisingly, among the 12/280 patients (4.2%) with familial variants of melanoma, multiple melanomas were not found in a increased frequency. In patients with DNS (regardless of whether sporadic or familial) the frequency of multiple melanomas is higher: in patients with solitary melanomas DNS was found in 27/257 (10.5%), while in patients with multiple melanomas DNS was diagnosed in 11/23 (47.8%) (P less than 0.0005). In both groups (solitary and multiple melanomas) the mean age of patients with DNS was around 10 years lower. The frequency of additional primary malignancies in patients with cutaneous melanomas was 8.6%, and did not vary according as whether patients had solitary or multiple melanomas with or without DNS.     

Genetic variations of patients with familial or multiple melanoma in Southern Brazil

Background Patients with familial melanoma or multiple primary melanoma represent a high‐risk population to hereditary melanoma. Mutations in susceptibility genes, such as CDKN2A, CDK4 and MC1R, have been associated with the development of melanoma. Objectives The purpose of this study was to determine the genotypic background of patients with familial and/or multiple melanoma in southern Brazil. Methods This study analysed 33 cases (5 patients with multiple primary melanoma and 28 patients from families with at least two well documented cases) and 29 controls. Genomic analysis of CDKN2A and CDK4 genes by PCR‐SSCP analysis and sequencing and direct sequencing of MC1R were performed in all individuals. Results No functional mutations in CDKN2A or CDK4 were detected in the 62 individuals. Infrequent variants in polymorphic loci of CDKN2A gene were identified in 15 participants (24.2%) and 24/33 (72.8%) cases and 19/27 (70.4%) controls reported at least one infrequent variant in MC1R (P = 0.372). Furthermore, a non‐significant tendency towards an association between melanoma risk and MC1R variants G274A and C451T and a non‐significant linear tendency to the number of infrequent high‐risk variants in MC1R were observed. Conclusions These results suggest that in southern Brazilian population, CDKN2A or CDK4 germinal alterations may have a weaker influence than previously thought and environmental risk factors may play a central role in melanoma susceptibility. However, considering the tendency observed for gene MC1R, low‐penetrance genes may be a relevant aetiological factor in southern Brazil with fair skin population and high sunlight exposure.     

Nucleolar organizer regions in malignant melanoma and melanocytic nevi. Comparison of two counting methods

Using a silver staining technique, we studied nucleolar organizer regions (AgNOR) in paraffin sections of junctional nevi, compound nevi, intradermal nevi, blue nevi, dysplastic nevi, Spitz nevi, lentigo maligna, malignant melanomas in nevus, superficial spreading melanomas, and nodular melanomas. Two methods of counting black dots within nuclei were employed. One method was to count the discrete black dots within the nuclei, including the tiny black dots seen within the nucleolus; the second method did not take into account the subsidiary cluster of tiny black dots seen within the nucleolus, instead treating these dots as a single structure. Whichever method we used, a significant difference was found between the pooled mean AgNOR numbers for benign and malignant lesions. We found an overlap, however, between benign, in particular Spitz and dysplastic nevi, and malignant lesions when considering individual counts of AgNOR using both methods. We conclude that studying AgNOR does not seem to be a useful technique to differentiate Spitz and dysplastic nevi from malignant melanomas.