Etiology

• 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). 

Epidemiology

• 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

• 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

• 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.

Testing

• 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.

• UV (sun) exposure
• Fair skinned, Fitzpatrick skin type I-III
• Genetic predisposition (dysplastic nevus syndrome)
• Lesions predisposed to transformation: Nevus of Ota or cellular blue nevus or dysplastic nevus
• Genetic syndromes

• Lentigo maligna
• Nevus
• Lentigo senilis
• Pigmented basal cell carcinoma
• Pigmented seborrheic keratosis

Natural history

• Melanoma greater than T2b AJCC 7th edition staging is correlated with shorter time to progression and nodal and distant metastasis
• Overall rate of lymph node metastasis is approximately 10% and distant metastasis is can occur up to 7.7%
• Breslow thickness and Clark level are independent predictors of survival (Esmaeli, OPRS 2000)

Local treatment

• Wide local excision, 5mm margin recommended, with delayed reconstruction after margins status is confirmed on paraffin embedded (permanent) processing
• Some surgeons advocate 10 mm margins for tumors with Breslow thickness of 2 mm or greater (Esmaeli, OPRS 2003; Rene, Eye 2013)
• Alternative tissue processing described use of immunochemical staining on frozen section not yet validated in large scale study
• Sentinel lymph node biopsy should be considered for patients with thick melanoma

Sentinel lymph node biopsy

• Indications: Eyelid melanoma with Breslow thickness > 2 mm (Savar, Ophthalmology 2009) or ulceration on histopathology
• Treatments for a positive SLN: Complete neck dissection, possible radiation if more than 2 positive nodes or extracapsular extension; and consider for trials for Stage III melanoma.

Radiation

• High dose adjuvant radiation may be used in desmoplastic melanoma after surgery
• Radiation therapy is considered in the case of positive nodes on neck dissection after a positive sentinel lymph node is identified
• Used for palliative therapy when metastasis to brain, bone or lymph nodes

Treatment of systemic metastasis

• Traditionally cytotoxic chemotherapy, such as carboplatin, paclitaxel, and dacarbazine wereused for metastatic disease
• Biochemotherapy, interferon or interleukin-2, may have higher efficacy but higher toxicity
• BRAF inhibitors such as vemurafenib and debrafenib and MEK inhibitors such as trametinib are approved for use in surgically unresectable or metastatic melanoma

Other management considerations

• Molecular testing for BRAF
• Tumor infiltrating lymphocytes collection for experimental immunotherapy in patients with metastasis

Local recurrence

• Rate of local recurrence after complete excision reported from less than 1% up to 25% (Chan, Ophthalmology 2007)
• Patient should be followed every 3 months for the first year, followed by every 6 months the second year, then yearly for 5 years
• Palpation for neck lymphadenopathy and inspection of all four eyelids, including eversion of all four lids to examine the tarsal conjunctival, should be performed on all follow-ups
• Investigation with neck ultrasound or CT of the neck and CT chest/abdomen/pelvis should be utilized for patients with high risk melanoma (Breslow > 1.5mm with ulceration) or if palpable neck lymphadenopathy
• Nodal metastasis found during the follow-up is treated as described above for patients with a positive SLN.

• Loss of vital ocular adnexal structures such as lacrimal drainage system
• Prevention is not always possible, but in case of partial loss of canaliculus, primary reconstruction using either mono-canalicular or bi-canalicular stent may eliminate need for further surgery
• Conjunctivodacryocystorhinostomy with Jones tube if significant loss of both canaliculi may be necessary but should be delayed until final pathology is available
• Lagophthalmos from ectropion can be managed with lateral tarsal strip procedure or in the case of cicatricial ectropion, full-thickness skin graft may be needed
• Diplopia may result from direct damage or cicatricial changes when extensive orbital dissection is needed for tumor excision
• Facial nerve paralysis as a result of lymph node dissection can be managed with aggressive lubrication in mild cases
• Surgical management should include gold weight implant, ectropion repair with lateral tarsal strip and tarsorrhaphy
• Loss of the globe due to extensive, multiple recurrent disease is rare but may not be avoidable when there is significant loss of periocular soft tissue

• Local tumor invasion of orbit can lead to diplopia, vision loss (orbital compartment syndrome or direct tumor compression of optic nerve)
• Local tumor invasion of lacrimal drainage system can lead to symptoms of epiphora
• Local tumor invasion of trigeminal nerves can cause facial pain or numbness
• Metastasis – in-transit, regional/nodal, distant

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