Melanoma of the Eyelid

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)
• In one recent study, survival outcomes were significantly influenced by age, tumor stage, socioeconomic status, and facility characteristics (high-volume centers confer a survival advantage) (Robbins 2025)

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
• Immunotherapy has been used for locally advanced (particularly when the orbit is involved) or metastatic disease (Wladis 2025)

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

1. National Comprehensive Cancer Network, www.nccn.org
2. National Cancer Institute, www.cancer.gov
3. AAO, Basic and Clinical Science Course. Section 4: Ophthalmic Pathology and Intraocular Tumors; Section 7: Orbit, Eyelids and Lacrimal System, 2013-2014.
4. American Cancer Society. “What are the key statistics about melanoma?”. Available at: http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics. Accessed April 29, 2015.
5. Chan FM, O’Donnell BA, Whitehead K, Ryman W, Sullivan TJ. Treatment and outcomes of malignant melanoma of the eyelid: A review of 29 cases in Australia. Ophthalmology. 2007;114(1):187-92
6. Cook Jr BE and Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in olmsted county, minnesota. Ophthalmology. 1999;106(4):746-50.
7. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54
8. Esmaeli B. Ophthalmic Oncology. M.D. Anderson Solid Tumor Oncology Seires. New York: Springer, 2011.
9. Esmaeli B, Wang B, Deavers M, Gillenwater A, Goepfert H, Diaz E, Eicher S. Prognostic factors for survival in malignant melanoma of the eyelid skin. Ophthal Plast Reconstr Surg. 2000;16(4):250-7.
10. Esmaeli B, Youssef A, Naderi A, et al. Margins of excision for cutaneous melanoma of the eyelid skin: the Collaborative Eyelid Skin Melanoma Group Report. Ophthal Plast Reconstr Surg. 19: 96–101, 2003.
11. Friedlander P, Hodi FS: Advances in targeted therapy for melanoma. Clin Adv Hematol Oncol. 2010; 8:619-27. 
12. Garbe C and Leiter U. Melanoma epidemiology and trends. Clin Dermatol. 2009; 27(1):3-9.
13. Kauffman RM and Chen SL. Workup and staging of malignant melanoma. Surg Clin North Am. 94: 963-72, 2014.
14. Mathew R., and Messina J.L.: Recent advances in pathologic evaluation and reporting of melanoma. Semin Oncol. 39: 184-191, 2012.
15. Milman T and McCormick SA. The molecular genetics of eyelid tumors: Recent advances and future directions. Graefe’s Arch Clin Exp Ophthalmol. 251: 419-33, 2013.
16. Rene C. Oculoplastic aspects of ocular oncology. Eye, 27: 199-207, 2013.
17. Robbins JO, Huck NA, Khosravi P, et al. Trends in demographic, clinical, socioeconomic, and facility-specific factors linked to eyelid melanoma survival: a national cancer database analysis. Ophthalmic Plast Reconstr Surg. Published online January 6, 2025.
18. Savar A, Ross MI, Prieto VG, Ivan D, Kim S, Esmaeli B. 2009. Sentinel lymph node biopsy for ocular adnexal melanoma: Experience in 30 patients. Ophthalmology 116(11):2217-23.
19. SEER Stat Fact Sheet: Melanoma. From the National Cancer Institute’s Surveillance, Epidemiology, and End Results Database. Available at: http://seer.cancer.gov/statfacts/html/melan.html. Accessed April 29, 2015.
20. Sondak V.K., Taylor J.M., Sabel M.S., et al: Mitotic rate and younger age are predictors of sentinel lymph node positivity: lessons learned from a generation of a probabilistic model. Ann Surg Oncol. 11: 247-258, 2004.
21. Takata M: Identifying BRAF and KIT mutations in melanoma. Expert Rev Dermatol. 2013; 8:171.
22. Wladis EJ, Rothschild MI, Bohnak CE, Adam AP. New therapies for unresectable or metastatic cutaneous eyelid and orbital melanoma. Orbit. 2025;44(1):137-143.
23. Woodman SE, Davies MA. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem. Pharmacol. 2010; 80(5): 568–574.
24. Yin V, Esmaeli B. Eyelid tumors: Sentinel Lymph Node Assessment and Biopsy for Eyelid and Conjunctival Malignancies. In: Clinical Ophthalmic Oncology – Eyelid and Conjunctival Tumours. 2nd. Ed(s) Pe’er J Singh AD. Springer 111-124, 2014.
25. Yin VT, Warneke CL, Merritt HA, Esmaeli B. Number of excisions required to obtain clear margins and prognostic value of AJCC T category for patients with eyelid melanoma. Br J Ophthalmol. In Press.