Page 881 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

Benign and Premalignant Tumors 867

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Figure 23–20 Dysplastic nevus. A, Numerous irregular nevi on the back of a patient with the dysplastic nevus syndrome. The lesions usually are
greater than 5mm in diameter and have irregular borders and variable pigmentation (inset). B, Compound dysplastic nevi feature a central dermal
component with an asymmetric “shoulder” of exclusively junctional melanocytes (lentiginous hyperplasia). The former corresponds to the more pig-
mented and raised central zone (see A, inset), and the latter, to the less pigmented flat peripheral rim. C, Other important features are cytologic atypia
(irregular, dark-staining nuclei) and characteristic parallel bands of fibrosis—part of the host response to these lesions.

any particular nevus, dysplastic or otherwise, will develop capacity to metastasize, and do not induce angiogenesis.
into melanoma is exceedingly low, and these lesions are With time, a vertical growth phase supervenes, in which
best viewed as markers of melanoma risk. the tumor grows downward into the deeper dermal layers
as an expansile mass lacking cellular maturation (Fig. 23–21, E).
Melanoma This event often is heralded by the development of a nodule
in a previously flat lesion (Fig. 23-22, A) and correlates with
Melanoma is less common but much more deadly than the emergence of a clone of cells with metastatic potential.
basal or squamous cell carcinoma. Today, as a result of
increased public awareness of the earliest signs of skin Most melanomas occur sporadically, but a few are heredi-
melanomas, most melanomas are cured surgically. None- tary (with reported rates ranging from less than 5% to 10%).
theless, the incidence of these lesions has increased dra- Molecular genetic analysis of familial and sporadic cases has
matically over the past several decades, at least in part as provided important insights into the pathogenesis of mela-
a result of increasing sun exposure and/or higher detection noma. As with other tumors, malignant transformation of
rates resulting from vigorous surveillance. melanocytes is a multistep process that involves activating
mutations in proto-oncogenes and loss-of-function mutations
PATHOGE NESIS in tumor suppressor genes. Germline mutations in the
CDKN2A gene (located on 9p21) are found in as many as 40%
As with other cutaneous malignancies, sunlight plays an of the rare individuals who suffer from familial melanoma.
important role in the development of melanoma. The inci- This gene encodes the tumor suppressor p16, a cyclin-
dence is highest in sun-exposed skin and in geographic locales dependent kinase inhibitor that regulates the G1-S transition
such as Australia where sun exposure is high and much of of the cell cycle in a retinoblastoma protein–dependent
the population is fair-skinned. Intense intermittent exposure fashion (Chapter 5). The CDNK2A gene also is silenced in
at an early age is particularly harmful. Recent “deep sequenc- some sporadic tumors by methylation. Somatic activating
ing” studies have confirmed that tumor genomes contain mutations in the proto-oncogenes BRAF or NRAS are observed
thousands of acquired mutations, most bearing a signature in a high proportion of melanomas. These mutations, which
consistent with UV-induced DNA damage. Sunlight, however, promote cellular proliferation and survival by activating the
is not the only predisposing factor; hereditary predisposition extracellular signal–regulated protein kinase (ERK) pathway,
also plays a role, as already discussed under familial dysplastic generally are mutually exclusive, since BRAF functions down-
nevus syndrome. stream of RAS. Also frequently seen is loss of function of the
tumor suppressor PTEN, an important negative regulator of
As with other cancers, it is believed that melanoma may PI3K-AKT pathway, which also promotes growth and sur-
arise in a stepwise fashion from precursor lesions (Fig. 23–21). vival. Some melanomas, particular those arising in acral and
Key phases of tumor development are marked by mucosal sites, have activating mutations in the c-KIT receptor
radial and vertical growth. Radial growth describes the tyrosine kinase. Agents that selectively inhibit mutant BRAF
initial tendency of a melanoma to grow horizontally within and c-KIT have produced dramatic responses in patients with
the epidermis (in situ), often for a prolonged period (Fig. metastatic tumors with BRAF and c-KIT mutations, respec-
23–21, D). During this stage, melanoma cells do not have the tively, an encouraging example of molecularly targeted
therapy in an otherwise hopeless disease.