What is the pathophysiology of cutaneous melanoma?

Updated: Oct 13, 2020
  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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Answer

The sequence of events in which normal melanocytes transform into melanoma cells, referred to as melanomagenesis, is poorly understood. It likely involves a multistep process of progressive genetic mutations that (1) alter cell proliferation, differentiation, and death and (2) impact susceptibility to the carcinogenic effects of ultraviolet radiation. [2] Recent data suggest multiple pathways of melanoma pathogenesis, with melanomas in sun-protected skin (trunk) developing in association with a high nevus count and intermittent ultraviolet radiation as opposed to those developing on sun-exposed skin in patients with low nevus counts and chronic sun exposure. [3, 4]

Differences in frequency of BRAF or NRAS mutations are also related to patterns of sun exposure, with BRAF mutations more common in intermittently UV-exposed skin compared with chronically sun exposed skin or relatively unexposed skin (eg, acral sites, mucosal sites), which more frequently demonstrate KIT mutations. [4, 5]

A meta-analysis by Lee et al demonstrated that the prevalence of these mutations may also depend on melanoma histologic subtype. [6]

Primary cutaneous melanoma may develop in precursor melanocytic nevi (ie, common, congenital, and atypical/dysplastic types), although more than 70% of cases are believed to arise de novo (ie, not from a preexisting pigmented lesion).

The development of melanoma is multifactorial and appears to be related to multiple risk factors, including fair complexion/sun sensitivity, excessive childhood sun exposure and blistering childhood sunburns, an increased number of common or atypical/dysplastic nevi (moles), a family history of melanoma, the presence of a changing mole or evolving lesion on the skin, and, importantly, older age. [7, 8, 9]


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