- Overview - malignant transformation of skin melanocytes is most commonly from UV induced DNA damage
- Proliferative signals are activated (i.e., BRAF, KIT oncogenes)
- Tumor suppressor genes become dysregulated and inactivated (Milman, Graefe's Arch Clin Exp Ophthalmol 2013)
- Malignancy may develop de novo or in predisposed lesion such as cellular blue nevus (Nevus of Ota) or dysplastic nevus
- BRAF oncogene - Melanomas arising after intermittent, rather than chronic, UV exposure are more likely to harbor BRAF mutations.
- The RAS–RAF–MEK–ERK–MAP kinase pathway mediates cellular responses to growth signals.
- Three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by RAS binding.
- Activating mutations in BRAF occur in approximately 50% of melanomas. Other members of the Raf family are ARAF and CRAF
- All BRAF mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%.
- Activated BRAF proteins have elevated kinase activity and RAS function is not required for the growth of cancer cell lines with the V599E mutation.
- Other common BRAF mutations in melanoma, found in the same codon, are V600K (about 16% of mutations in melanoma) and V600D/R.
- These less common variants are found at slightly higher rates in melanomas arising in older patients (Davies, Bignell 2002).
- KIT oncogene - melanomas in skin with chronic sun induced damage infrequently have mutations in BRAF and NRAS but uniquely harbor activating mutations in KIT (Friedlander, Hodi 2010).
- The KIT proto-oncogene encodes a tyrosine-kinase transmembrane receptor in the MAPK pathway that regulates cellular proliferation (Takata, 2013).
- Only 10-20% harbor KIT activation.
- Over 20 KIT mutations have been identified in melanoma, most are point mutations.
- Most common is leucine to proline substitution at codon 576 of exon 11 which comprises one third of KIT mutations in melanoma (Woodman, Davies 2010).
- Accounts for less than 1% of eyelid malignancies (Cook, Ophthalmology 1999)
- More common in older individuals, mean age at presentation in the 6th decade (Esmaeli, OPRS 2000)
- Rarely occurs in non-Caucasians (Garbe, Clin Dermatol 2009)
- Increasing incidence for melanoma overall by 3 fold from 1970s to beginning of 2000 (Garbe, Clin Dermatol 2009)
- Increasing incidence in each of the past four decades (Kauffman, Surg Clin North Am 2014)
- Equal gender distribution (Esmaeli, OPRS 2000)
- Melanoma is the fifth most common cancer in the United States (incidence = 76,100 cases/year, 9,710 deaths in 2014) (American Cancer Society 2015; SEER Stat Fact Sheet 2015).
- History of other skin cancer and cell type
- Characteristics of lesion to inquire include duration, growth, bleeding
- History of sun or UV exposure (tanning bed use)
- Immune suppression
- Light skin/hair (Milman, Graefe's Arch Clin Exp Ophthalmol 2013)
- Genetic syndromes (xeroderma pigmentosum, Wiskott-Aldrich)
- Clinical features indicative of malignancy include lid margin destruction, ulceration, madarosis, irregular boarder, heterogeneous pigmentation (Figures 1 and 2)
- Rarely can present without pigmentation (i.e., amelanotic melanoma)
Figure 1. Eyelid melanoma. Image courtesy Brett Davies, MD.
Figure 2. Eyelid melanoma. Image courtesy Jennifer Sivak, MD.
- Incisional biopsy of the melanocytic lesion and examination under paraffin embedded tissue is gold standard for diagnosis
- High risk histological features include: Breslow thickness, ulceration, mitotic figures, perineural invasion, lymphovascular invasion, satellitosis and regression
- Depth of invasion is the single best predictor of survival (Kauffman, Surg Clin North Am 2014)
- High dermal mitotic rate portends decreased survival (Mathew, Semin Oncol 2012; Sondak, Ann Surg Oncol 2004)
Testing for staging, fundamental impairment
- AJCC 7th edition Cancer Staging Manual defines TNM categories for melanoma
- T-stage based on Breslow thickness and ulceration
- Nodal category refers to nodal metastasis:
- Regional nodal basin at risk for metastasis include the parotid, submandibular, and cervical nodes
- Evaluation may entail palpation, imaging studies such as ultrasound or CT guided fine needle aspiration biopsy for suspicious nodes
- Alternatively, sentinel lymph node (SLN) biopsy can be performed for high risk lesions
- Baseline CT of chest/abdomen/pelvis and MRI of brain may also be appropriate for lesions greater than 2 mm thickness or with histological ulceration.
- These tests should be repeated periodically in high risk patients or in patients with positive SLNs
- When clinical exam suspicious for orbital invasion, orbital CT or MRI will assist in surgical planning.