๐ ็ธฝ็ฎ้ ๏ฝ ๐ ่ฑๆๅๆ๏ผๆฌ็ฏ๏ผ ๏ฝ ๐ ๅฎๆด็ฟป่ญฏ ๏ฝ โญ ็ฒพ่ฏ็ญ่จ
PATHOPHYSIOLOGY
PATHOPHYSIOLOGY
Several genetic alterations have been implicated in the development of DN. For example, mutations in a cell cycle regulator, p16INK4a appear to be involved in tumorigenesis and in DN.10 Carriers of p16 mutations are more likely to have greater than 100 nevi, according to a study by Bishop et al. of five families with these mutations.11 Other alterations in BRAF, NRAS, and mismatch repair enzymes are also present in DN, but these mutations can also be found in both melanoma and CN.10,12โ15 When gene expression patterns were examined by Scatolini et al. among CN, DN, and melanomas, it was noted that there are many similarities in gene expression between DN and CN including those involved with mitosis, apoptosis, and transcriptional regulation.16 Nevertheless, DN demonstrate higher rates of Ki-67 positivity, a marker of proliferation, relative to CN. Levels of cyclin D1 and D3, which indicate cell division, are intermediate for DN between what is observed for CN and melanoma.17,18 Thus, DN may proliferate more actively than CN but not as significantly as melanoma.19 An autosomal dominant inheritance pattern for the nevus phenotype in melanoma-prone families has been postulated, with many of these families showing mutations at the CDKN2A locus.20,21
Ultraviolet (UV) exposure has also been postulated to lead to the development of DN. However this is controversial, as some studies have failed to find a relationship between sun exposure and DN,22 while another study found that CAN density was greatest on skin that was intermittently exposed to sunโso-called traumatizing exposureโintense exposure that exceeds the natural resistance of the skin.23 Finally, alterations in the host immune system may be related to the development of multiple DN (โeruptive DNโ). This may occur in the context of immunosuppression for organ transplants, chemotherapy, systemic immunosuppression from HIV, and certain hematologic malignancies.24โ27