Disease relevance of Dysplastic Nevus Syndrome

• The hereditary dysplastic nevus syndrome (DNS) is a well-characterized disorder in which affected individuals have increased numbers of premalignant (dysplastic) nevi and a markedly increased risk of developing cutaneous melanoma [1].
• Furthermore, we have analyzed the expression of versican in human melanocytic nevi and melanoma: 10 benign melanocytic nevi, 10 dysplastic nevi, 11 primary malignant melanomas, and 8 metastatic melanomas were tested [2].
• We have searched the frequency of p16 and p53 deletion in nine dysplastic nevi and 13 benign intradermal nevi with five microsatellite markers [3].
• The recently described method of staining nucleolar organizer regions (NOR) with colloidal silver nitrate was applied to the paraffin sections of five junctional nevi, 13 compound nevi, seven Spitz nevi, nine cellular blue nevi, 11 dysplastic nevi, seven malignant lentigines, 12 superficial spreading melanomas, and 14 secondary melanomas [4].
• In this study, p16/CDKN2A gene expression was determined by reverse transcription polymerase chain reaction in seven skin cancer patients, in one dysplastic nevus patient and in seven healthy individuals, prior to UVB exposure and at various times after application of one minimal erythema dose (MED) [5].

High impact information on Dysplastic Nevus Syndrome

• We have analysed CDKN2 coding sequences in 15 Dutch familial atypical multiple mole-melanoma (FAMMM) syndrome pedigrees, and identified a 19 basepair (bp) germline deletion in 13 of them [6].
• 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 [7].
• Detection of p53 mutations in benign and dysplastic nevi [8].
• Effects of topical tretinoin on dysplastic nevi [9].
• We report the results of a pilot study of topical retinoic acid in patients with dysplastic nevi [9].

Chemical compound and disease context of Dysplastic Nevus Syndrome

• In parallel with these findings, co-culture of T cells with interferon-treated cells of a dysplastic nevus and a radial phase melanoma led to augmented T cell incorporation of tritiated thymidine, and this stimulation was inhibited with a monoclonal antibody to HLA-DR antigens [10].
• Computerized image analysis was used to assess nuclear atypia in 24 dysplastic nevi (DN), 19 CN (CN), and five thin melanomas [11].
• RESULTS: Persons in high versus low quintiles of energy-adjusted vitamin D, alpha-carotene, beta-carotene, cryptoxanthin, lutein, and lycopene had significantly reduced risk for melanoma (ORs < or = 0.67), which remained after adjustment for presence of dysplastic nevi, education, and skin response to repeated sun exposure [12].
• Effect of oral isotretinoin on dysplastic nevi [13].
• Melanocytic lesions from these patients, including primary cutaneous melanomas, dysplastic nevi, and benign nevi, contained large numbers of estrogen and progesterone binding cells [14].

Biological context of Dysplastic Nevus Syndrome

• Most families with familial atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden dermatology clinic share the same p16-inactivating deletion (p16-Leiden) [15].
• Our goal was to examine the joint effects of MC1R variants and other potential risk factors [total nevi, dysplastic nevi, pigmentary traits (skin, hair and eye color), skin reactions to sunlight, and degree of sun exposure] on CDKN2A penetrance [16].
• Genetic heterogeneity in the familial atypical multiple mole melanoma (FAMMM) syndrome and other single gene disorders that predispose to malignant melanoma are particularly stressed [17].
• The T1796A single point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage of malignant melanomas and benign melanocytic lesions such as congenital nevi, compound nevi, intradermal nevi and dysplastic nevi [18].
• This study investigated the immunoreactivity of the cell proliferation marker MIB1-Ki67 in 23 compound nevi, 17 dysplastic nevi, 8 Spitz nevi (SN), and 24 malignant melanomas (MMs) and evaluated its ability in separating benign nevi from MMs [19].

Anatomical context of Dysplastic Nevus Syndrome

• We studied the effect of biologically relevant doses (comparable to 2-3 MED (minimal erythemal dose) for in vivo irradiated full-thickness skin) of monochromatic UVB light of 302 nm on cultured melanocytes derived from foreskin, common melanocytic nevi, and dysplastic nevi [20].
• In contrast to HMB.45, S-100 protein labeled nevomelanocytes, regardless of whether they were within the epidermis or dermis, although, in half of the dysplastic nevi, the reaction was heterogeneous, with some atypical cells failing to stain [21].
• Major risk factors for melanoma include many nevi, especially dysplastic nevi, fair pigmentation, freckling, poor tanning ability, and germ line mutations in the CDKN2A, CDK4, or MC1R genes [22].
• BACKGROUND: Previous studies suggest that the familial atypical multiple-mole melanoma (FAMMM) syndrome may predispose affected families to nonmelanoma carcinomas, including adenocarcinoma of the pancreas [23].
• Multiple pigmented lesions including benign lentigines, typical nevi, and dysplastic nevi from 3 patients with the dysplastic nevus syndrome contained giant melanosomes (GM) [24].

Gene context of Dysplastic Nevus Syndrome

• The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM [25].
• However, there clearly are melanoma-prone families that do not express the dysplastic nevus trait, and some of the families linked to CDKN2A also present with dysplastic nevi [26].
• CONCLUSIONS: Our study shows that IGFBP2 expression increases from benign and dysplastic nevi to primary and metastatic melanomas and suggests that it may play a role in melanoma progression [27].
• NRAS codon 61 mutations were also detected in dysplastic nevi and in an in situ melanoma, suggesting a role for such mutations during early melanoma development [28].
• Immunohistochemical analysis showed that SPARC was strongly expressed in 100% of primary melanomas (7 of 7) and metastatic melanomas (29 of 29), moderately expressed in most of the positive dysplastic nevi (13 of 14), and only weakly expressed in nevocellular nevi (4 of 25) [29].

Analytical, diagnostic and therapeutic context of Dysplastic Nevus Syndrome

• Immunohistochemistry on paraffin-embedded tissue sections of 159 cases revealed a significant increase in intensity of ETB receptor expression from common nevi over dysplastic nevi and primary MM to metastatic MM [30].

References