Melanoma is the most dangerous type of skin cancer, occuring due to malignant tumours which originate in melanocytes. Melanocytes reside in the basal layer of the epidermis, and produce melanin, a pigment that absorbs ultraviolet radiation (UVR). 1 Melanoma is mainly caused by intense UVR exposure in conjunction with genetic mutations. As the skin is exposed to UVR, melanin and repair mechanisms such as nucleotide excision repair (NER) are available to protect the DNA from structural damage. However, in the case of excessive exposure to UVR, DNA rearrangements can exceed the repair capacity. 2 Current research is investigating genes that may be targeted by DNA rearrangement in melanoma, and there is no definite answer as to which genes are mutated by UVR. Recent research suggests that some tumour suppressor genes or cell growth regulation genes may be mutated, leading to neoplastic growth of melanocytes. This pathophysiology figure includes multiple models undergoing research at this time.
MELANOMA PATHOPROFILE AUTHORS
ARLINDA DENG NICOLE FALZONE
ARTIST MELISSA LEE
BENIGN NEVUS Melanocytes grow directly above the basement membrane in clusters. Here, the melanocyte cells are normal in structure.6
NER failure, or inability to cope with the DNA rearrangement capacity, leads to uncorrected DNA damage. 2 Different genes that may undergo DNA rearrangement to cause proliferation of melanocytes include:
2.
Rass K, Reichrath J. UV damage and DNA repair in malignant melanoma and nonmelanoma skin cancer. Adv Exp Med Biol. 2008;624:162–78.
3.
Pfeifer GP, Besaratinia A. UV wavelength-dependent DNA damage and human non-melanoma and melanoma skin cancer. Photochem Photobiol Sci. 2012 Jan;11(1):90–7.
4.
Melanoma KnowledgeBase | GNA11 and GNAQ. http://www.cancercommons.org/pa tients-caregivers/melanoma/gna11-and-gnaq/ (accessed 17 October 2014).
5.
Clark Jr, W. H.et al. (1984). A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Human Pathology, 15(12), 1147-1165.
6.
Meier, F. et al. (2000). Human melanoma progression in skin reconstructs: biological significance of bFGF. The American Journal of Pathology, 156(1), 193-200.
7.
Dong, J. et al. (2003). BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Research, 63(14), 3883-3885.
8.
Hsu, M. Y.et al. (1998). Adenoviral gene transfer of β3 integrin subunit induces conversion from radial to vertical growth phase in primary human melanoma.The American Journal of Pathology, 153(5), 1435-1442.
9.
Liu, Z., Wang, F., & Chen, X. (2008). Integrin αvβ3‐targeted cancer therapy. Drug Development Research, 69(6), 329-339.
10. National Cancer Institute: PDQ® Melanoma Treatment. Bethesda, MD: National Cancer Institute. http://cancer.gov/cancertopics/pdq/treatment/melanoma/Patient (accessed 17 October 2014).
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PRIMARY MELANOMA RADIAL GROWTH PHASE (RGP) a) Melanocytes grow outwards in the epidermis, becoming concentrated above the epidermal basement membrane. b) In later stages, sometimes termed ‘the invasive RGP,’ a few non-dividing melanocytes grow in the dermal papillae. An important characteristic of the RGP is its lack of metastatic and tumourigenic activity.5
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PRIMARY MELANOMA VERTICAL GROWTH PHASE (VGP) a) The proliferating melanocytes advance into the dermis. Melanocytes in the VGP produce bFGF, a fibroblast growth factor that can stimulate the migration of RGP melanoma into the VGP.6 b) Increased BRAF oncogenic mutation levels in VGP melanoma versus RGP melanoma suggest that this gene mutation could be an indicator of cancer progression.7 c) The VGP is associated with an increased expression of the β3 integrin subunit of the αv β3 vitronectin receptor. This receptor is involved in tumour angiogenesis and can increase tumour growth in vivo.8,9
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METASTATIC MELANOMA In advanced stage melanoma, metastases of the primary tumour travel through the blood or lymph system to different areas of the body. As the primary tumour invades the dermis during the VGP, drainage into the sentinel lymph node can cause melanoma cells to travel throughout the lymphatic system to visceral sites of melanoma metastases.10
Metastasis
Tortora GJ. Principles of Anatomy & Physiology, Volume 1. New York: Wiley-Blackwell; 2011.
DYSPLASTIC NEVUS An atypical mole appears, which contains melanocytes with abnormal structure and shows a tendency to become malignant.6
VGP
1.
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RGP
a) The tumour suppressor gene p16/CDKN2 is often seen with the characteristic UVB-induced C to T transition mutation. 3 b) The BRAF gene is frequently mutated in melanoma. Though the mutation is a T to A transversion rather than a pyrimidine dimer formation, researchers are still investigating whether this is a sunlight-induced mutation. 3 c) Mutations in the GNAQ and GNA11 genes, responsible for regulating cell division, are found to carry the signature of pyrimidine dimer-induced C to T transition. 3,4
EPIDERMIS
Dysplastic Nevus
3
High energy from UVR promotes the formation of covalent bonds between adjacent pyrimidine bases to form a cyclobutane pyrimidine dimer. This usually occurs as thymine dimers, cytosine dimers, or cytosine-thymine dimers. 2
4
A G GT TG CATCTG TCCA ACG TAG AC
2
The skin is exposed to excessive UVR, and repair mechanisms are unable to cope. UVB, the type of UVR that is absorbed by the epidermal layer, causes the DNA to rearrange. 2
BASEMENT MEMBRANE
DERMIS
Benign Nevus
1
CLARK CLASSIFICATION OF TUMOR PROGRESSION 5