Malignant Melanoma
Key Points
Cutaneous malignant melanoma is an invasive tumor of malignant melanocytes
On the eyelid, malignant melanoma accounts for about 1% of all eyelid malignancies
On the eyelids, the nodular and lentigo maligna melanoma types are the most common
UV light in the pathogenesis of melanoma is well established
Approximately 50% of all cutaneous melanomas harbor BRAF and less commonly NRAS mutations
Cutaneous melanomas usually appear as asymmetric lesions with irregular borders, uneven distribution of color, diameters over 6 mm, and a history of growth
The treatment of choice is complete surgical excision with wide tumor-free margins
Radiotherapy is rarely used as a primary treatment but is used as an adjuvant therapy in cases of advanced nodal or primary disease following surgical resection
Cutaneous melanoma accounts for two-thirds of all deaths from skin cancer. Early diagnosis and treatment are critical to improved outcomes
Cutaneous malignant melanoma is an invasive tumor of malignant melanocytes. Worldwide, it is the 12th most common cancer and has an estimated age-standardized incidence rate of 3.0 per 100,000 population.1 The incidence varies in different populations, with the highest rates reported in Australia and New Zealand and the lowest rates in South-Central and South-Eastern Asia. The annual incidence is increasing and is estimated to continue to increase due to the increasing lifespan and aging of the population.2 While it accounts for only a small percentage of skin cancers, malignant melanoma is responsible for the majority of skin cancer-related deaths.3 On the eyelid, malignant melanoma accounts for about 1% of all eyelid malignancies, with an annual incidence of 0.6 per million white residents over the age of 20 years.3
Cutaneous melanoma has been classified into subtypes recognized by the World Health Organization (WHO)4 and less common variants.5 The four major subtypes and their relative incidences are superficial spreading melanoma (30%-60%), lentigo maligna melanoma (10%-40%), nodular melanoma (15%-35%), and acral lentiginous melanoma (5%-10%).5 More recently (2018), the WHO has classified melanomas into melanomas arising in sun-exposed skin and those arising at sun-shielded sites or those without known etiological associations with ultraviolet (UV) radiation exposure.4 Melanomas arising in sun-exposed skin are subdivided into those with low- or high-cumulative sun damage (CSD), as assessed by grading the degree of solar elastosis in a skin biopsy.4 Melanomas arising in sun-exposed skin are (1) low-CSD melanoma/superficial spreading melanoma; (2) high-CSD melanoma/lentigo maligna melanoma; and (3) desmoplastic melanoma.4 Melanoma arising at sun-shielded sites or those without known etiological associations with UV radiation exposure are malignant Spitz tumor, acral melanoma, mucosal melanoma, melanoma arising in a congenital nevus, melanoma arising in blue nevus, and uveal melanoma.4
Superficial spreading, lentigo maligna, nodular, and desmoplastic melanoma are the most common subtypes of eyelid cutaneous melanoma (Figures 136.1 and 136.2).6,7 In a review of clinical series of eyelid skin melanomas between 1990 and 2018, there were 297 invasive melanomas with approximately 35% superficial spreading, 31% lentigo maligna melanoma, 19% nodular, and 16% other melanomas.7 An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2016 identified 2257 patients with primary melanoma of the eyelid region, with 1380 in situ melanomas (61.1%) and 877 invasive melanomas (38.9%).7 In situ melanomas were 53.6% lentigo maligna, 3.2% superficial spreading melanoma, and 43.2% unknown subtype.7 The major subtypes of invasive melanomas were 20.9% lentigo maligna melanoma, 20.0% superficial spreading, 8.1% nodular, 2.1% desmoplastic, 1.7% spindle, and 45.4% unknown subtype.7 Eyelid skin melanomas can arise from congenital nevi, cutaneous moles, and excessive sun exposure. They are far more common in Caucasians,7 in those with a history of chronic sun exposure and severe sunburns, and in patients with dysplastic nevus syndrome. Eyelid lesions can be primary tumors or less commonly represent tumor extension from the conjunctiva, metastasis from a distant primary site, or even a metastasis from the contralateral choroid.8,9,10 The diagnosis of cutaneous melanoma may be difficult due to variability in its appearance. The clinical suspicion for lesions later histologically confirmed to be melanomas has been reported at between 15% and 57% and even lower for amelanotic variants.11,12 Approximately 80% of eyelid melanomas occur on the lower eyelid.13 Eyelid cutaneous melanoma may rarely extend posteriorly into the orbit.14
The amelanotic variant of cutaneous melanoma is a rare form characterized by the clinical absence of pigmentation.
Because of this, it is often diagnosed late. The incidence of amelanotic melanoma has been estimated at approximately 2% to 8% of all melanoma cases,15 but in a series of 24 patients with eyelid skin melanoma, Garner et al reported that 50% were amelanotic.16 Any of the four histopathological subtypes can be amelanotic. In general, amelanotic melanomas may present as erythematous macules or plaques or have a scaly appearance.17,18,19 They may also resemble inflammatory lesions such as eczema, psoriasis, rosacea, and contact dermatitis17,20,21 or a variety of benign neoplasms such as nevi, hemangiomas, and seborrheic keratosis. Some lesions may mimic more common malignant tumors such as basal cell carcinoma or Bowen disease.21,22,23 There are no specific clinical criteria for diagnosing eyelid amelanotic melanomas,22 but dermatoscopy findings are helpful by showing diagnostic vascular patterns such as serpentine, irregular linear, pinpoint, and hairpin vessels.24,25
Because of this, it is often diagnosed late. The incidence of amelanotic melanoma has been estimated at approximately 2% to 8% of all melanoma cases,15 but in a series of 24 patients with eyelid skin melanoma, Garner et al reported that 50% were amelanotic.16 Any of the four histopathological subtypes can be amelanotic. In general, amelanotic melanomas may present as erythematous macules or plaques or have a scaly appearance.17,18,19 They may also resemble inflammatory lesions such as eczema, psoriasis, rosacea, and contact dermatitis17,20,21 or a variety of benign neoplasms such as nevi, hemangiomas, and seborrheic keratosis. Some lesions may mimic more common malignant tumors such as basal cell carcinoma or Bowen disease.21,22,23 There are no specific clinical criteria for diagnosing eyelid amelanotic melanomas,22 but dermatoscopy findings are helpful by showing diagnostic vascular patterns such as serpentine, irregular linear, pinpoint, and hairpin vessels.24,25
 FIGURE 136.1 Lentigo maligna. A, Flat, irregular pigmented lesion along the lateral eyelid mucocutaneous border. B, Irregular, variably pigmented conjunctival lentigo maligna on the eyelid margin and palpebral conjunctiva. C, Lightly pigmented, multicentric macules and small nodules at the lateral canthus and lateral cheek. D, Very diffuse, variably pigmented flat lesion on the medial canthus, lower eyelid, and nasal bridge. (A, Courtesy of Dr. Robert Kersten.) |
Conjunctival melanoma is distinct from cutaneous eyelid melanoma, but anatomically the posterior lamellae of the eyelids and the caruncle are conjunctival tissue, so any discussion of eyelid melanoma must include conjunctival lesions. Malignant melanoma of the conjunctiva is rare compared with uveal or cutaneous melanoma.26 Its incidence has been reported as 0.2 to 0.8 per million population in non-Hispanic Caucasians,27 with lower incidences in Hispanics, Blacks, Asians, and Native Americans.28 As with cutaneous melanoma, its rate has been increasing, and for Caucasian men in the United States, the age-adjusted incidence rate increased by 295% from 1973 to 1999.29 It is a potentially lethal tumor with an average 10-year mortality rate of 30%.27 These tumors occur primarily in the fourth to seventh decades of life, but rare cases have been described in children.30 The perilimbal bulbar conjunctiva is the area most commonly involved, although these tumors can occur on any conjunctival surface, including the eyelid and caruncle. In a recent multicenter international study of 288 patients with conjunctival melanoma, the melanoma involved the bulbar conjunctiva in 83.5% of eyes and was nonbulbar in 16.5% of eyes.31
 FIGURE 136.2 Spectrum of presentations of eyelid and conjunctival melanoma. A, Desmoplastic melanoma arising in a melanocytic nevus. B, Amelanotic melanoma of the lateral canthus. C, Multiple nodules of melanoma in the caruncle and palpebral conjunctiva arising in areas of PAM. D, Deeply pigmented melanoma involving the upper and lower eyelids and medial canthus. (B, Courtesy of Dr. Bita Esmaeli.) |
Conjunctival melanoma can arise de novo (19%), from a preexisting conjunctival nevus (7%), or from primary acquired melanosis (PAM) with atypia (74%).32,33,34 As with cutaneous melanomas, they may be amelanotic, where they can resemble other lesions such as squamous cell carcinomas, lymphoid hyperplasia, or pterygia.
Etiology and Pathogenesis
Cutaneous melanoma has a high burden of oncogenic mutations, most of which display an UV light signature.35,36 The role of UV light in the pathogenesis of melanoma is well established, and the frequency of melanoma in Caucasian populations correlates with latitude, and by implication, with sunlight intensity.13
Approximately 50% of all cutaneous melanomas harbor BRAF and less commonly NRAS mutations37 that contribute to oncogenesis by driving uncontrolled growth, suppressing apoptosis, and leading to melanoma invasion.38,39 Both BRAF and NRAS mutations occur as early events in oncogenesis, but neither alone seems sufficient to trigger malignant transformation.13 Also, about 35% of melanoma cell lines demonstrate deletions or mutations in the PTEN gene,40 and loss of function of the PTEN enzyme results in increased mitogenic signaling involved in cell proliferation, apoptosis, and immune activation.
Other factors involved in the pathogenesis of cutaneous melanomas have been suggested, but studies vary in research designs, protocols, and patient populations so that further research is needed. However, oxidative stress is involved in several chronic diseases and the progression of some cancers, including melanomas.41 Reactive oxygen species interact with inflammatory and immune processes and may participate in the melanogenic process.41 Dietary factors may also affect the development of melanoma, particularly citrus fruits and alcohol through enhancement of UV-induced apoptosis and increased photosensitivity.42
Clinical Presentation
Primary cutaneous melanoma evolves from a lesion of aberrant melanocytes with cytological atypia limited to the basal layers of the epidermis, as lentigo maligna, a form of melanoma in situ.7 These lesions typically appear clinically as flat to slightly elevated, irregular papules or plaques with variable pigmentation (Figures 136.1).7 They grow slowly over years or even dacades, often changing in color and morphology. Lentigo maligna progresses to early invasive melanoma as lentigo maligna melanoma with cellular invasion into the papillary dermis, and then to more advanced deeply invasive malanoma with the potential for hematogenous and lymphatic spread.
In the eyelids, melanoma is more frequently seen in the lower eyelid (56.8%), followed by the upper eyelid (13.3%), lateral canthus (10.3%), and medial cnathus (2.2%).7
 FIGURE 136.3 Melanoma involving the eyelid and adjacent areas of the face. A, Diffuse melanoma on the nose and lower eyelid. B, Multicentric melanoma at the lateral canthus and adjacent cheek. C, Widespread diffuse lightly pigmented melanoma of the lower eyelid and cheek. D, Multiple nodules of metastatic cutaneous melanoma in the eyelids, forehead, and face. (C, Courtesy of Dr. Bita Esmaeli.) |
Clinically, cutaneous melanomas usually appear as asymmetric lesions with irregular borders, uneven distribution of color, diameters over 6 mm, and a history of growth. They may show ameboid projections, eccentric expansion, and notching of the borders. Superficial spreading melanoma presents as a pigmented lesion that is flat to mildly elevated. It may go through a period of relatively flat horizontal growth but eventually tends to become elevated and nodular. Nodular melanomas present as a pigmented or amelanotic bulky irregular growth that rapidly increases in size and may be associated with ulceration and bleeding (Figure 136.2). On the eyelids, melanomas may involve the eyelid skin, mucocutaneous border, and adjacent areas of the face (Figure 136.3).
Acquired pigmented lesions on the periocular skin of middle-aged and elderly patients should raise the possibility of in situ melanoma (lentigo maligna) (Figure 136.1).43,44 These usually begin as a lightly pigmented macule that slowly enlarges over
several years or even decades. As many as 50% of these lesions may show histologic evidence of invasive lentigo maligna melanoma,45,46 and the risk increases with continued growth.
several years or even decades. As many as 50% of these lesions may show histologic evidence of invasive lentigo maligna melanoma,45,46 and the risk increases with continued growth.
Clinical diagnosis of eyelid melanoma is often difficult, and although in-person visual inspection greatly increases diagnostic accuracy compared with image-based evaluations, visual inspection alone is not entirely adequate. Diagnostic accuracy can be enhanced with ancillary tests such as dermoscopy,47 reflectance confocal microscopy, impedance spectroscopy, and digital epiluminescence microscopy.48,49,50,51 Each of these techniques has advantages over clinical observation alone, but all also have limitations and are not widely available. Conjunctival melanoma typically presents as a nontender flat to nodular pigmented lesion, often associated with increased vascularity, prominent feeder vessels, and progressive thickening (Figures 136.2C and 136.4).52,53 They may be associated with hemorrhage and bloody tears, and areas of ulceration. As with cutaneous and uveal melanoma, they may also be amelanotic.
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