Fig.24.20B-C ).Associatedalterationsalsooccurinthesuperficialdermis.Theseconsistofasparselymphocyticinfiltrate,releaseofmelaninpigmentthatisphagocytosedbydermalmacrophages(melaninincontinence),andlinearfibrosissurroundingepidermalnestsofmelanocytes.Thesedermalchangesareelementsofthehostresponsetotheselesions.
Unlike ordinary nevi, dysplastic nevi have a tendency to occur on body surfaces not exposed to the sun as well as on sun-exposed sites. Familial dysplastic nevus syndrome is strongly associated with melanoma, as the lifetime risk for the development of melanoma in affected individuals is close to 100%. In sporadic cases, only individuals with 10 or more dysplastic nevi appear to be at an increased risk for melanoma. Transformation of dysplastic nevus to melanoma has been documented, both clinically and histologically. However, such cases are the exception, as most melanomas appear to arise de novo and not from a preexisting nevus. Thus, the likelihood that any particular nevus, dysplastic or otherwise, will develop into melanoma is low, and these lesions are best viewed as markers of melanoma risk.
Fig. 24.20 Dysplasticnevus.(A)Numerousirregularnevionthebackofapatientwithdysplasticnevussyndrome.Thelesionsusuallyaregreaterthan5mmindiameterandhaveirregularbordersandvariablepigmentation(inset). (B)Compounddysplasticnevusfeaturingacentraldermalcomponentandanasymmetric“shoulder”ofexclusivelyjunctionalmelanocytes(lentiginoushyperplasia).Theformercorrespondstotheraised,morepigmentedcentralzoneseeninA (inset), andthelattercorrespondstothelesspigmentedflatperipheralrim.(C)Otherimportantfeaturesarecytologicatypia(irregular,dark-stainingnuclei)andcharacteristicparallelbandsoffibrosis.
Melanoma is less common but much more deadly than basal or squamous cell carcinoma. Today, as a result of increased public awareness of the earliest signs of skin melanomas, most melanomas are cured surgically. Nonetheless, the incidence of these lesions has increased dramatically over the past several decades, at least in part as a result of increasing sun exposure and/or higher detection rates resulting from vigorous surveillance.
As with other cutaneous malignancies, melanoma is mainly caused by UV light–induced DNA damage that leads to the stepwise acquisition of driver mutations. The incidence is highest in sun-exposed skin and in geographic locales such as Australia, where sun exposure is high and much of the population is fair-skinned. Intense intermittent exposure at an early age is particularly harmful. Hereditary predisposition also plays a role in an estimated 5% to 10% of cases, as already discussed under familial dysplastic nevus syndrome. For example, germ-line mutations in the CDKN2A locus (located on 9p21) are found in as many as 40% of the rare individuals who suffer from familial melanoma. This complex locus encodes two tumor suppressors: p16, a cyclin-dependent kinase inhibitor that regulates the G1-S transition of the cell cycle by maintaining the retinoblastoma (RB) tumor suppressor protein in its active state; and p14, which augments the activity of the p53 tumor suppressor by preventing its degradation.
Key phases of melanoma development are marked by radial and vertical growth. The earliest recognizable phase of melanoma development is proposed to consist of lateral expansion of melanocytes along the dermoepidermal junction (lentiginous hyperplasia and lentiginous compound nevus;
Fig. 24.21A-C ). This then progresses to the phase of melanoma in situ, which is marked by radial growth within the epidermis, often for a prolonged period (
Fig.