Jacqueline R. Carrasco
BASICS
DESCRIPTION
• The ocular adnexa contain virtually every tissue type and therefore, many types of malignant tumors can arise in this area.
• Early recognition and diagnosis of eyelid tumors are crucial to prevent local tissue destruction and distant spread.
• Metastasis can occur with many eyelid lesions and can cause significant morbidity and mortality.
• The most common malignant eyelid neoplasms include basal cell carcinoma (BCC), squamous cell carcinoma (SCC), sebaceous gland carcinoma, and malignant melanoma.
• Other extremely rare malignant tumors that can affect the eyelids are cutaneous T-cell and MALT lymphoma (see Ocular Adnexal Lymphoma chapter for further information), Merkel cell carcinoma, and Kaposi sarcoma.
EPIDEMIOLOGY
Incidence
• Varies by geographic region with degree of solar exposure.
• Approximately 5–10% of all skin cancers occur in the eyelid.
• Basal cell carcinoma: Approximately 14.35 cases per 100,000 population (80–90% of all malignant eyelid tumors).
• Squamous cell carcinoma: Between 0.09 and 2.42 cases per 100,000 population (5–10% of all malignant eyelid tumors).
• Non-basal cell and non-squamous cell tumors: Between 1.6 and 2.1 cases per 100,000 population (includes sebaceous gland carcinoma, 1–5% of all malignant eyelid tumors, malignant melanoma, 1% or less, and the very rare lymphoma, Merkel cell carcinoma and Kaposi sarcoma).
RISK FACTORS
Chronic sun exposure (the single most important risk factor), Caucasian race or fair skin color, older age, previous skin malignancy, immune dysfunction, focal dermatologic trauma (especially thermal burns), history of ionizing radiation, and exposure to trivalent inorganic arsenic.
GENERAL PREVENTION
Limit sun exposure, especially in childhood and adolescence.
PATHOPHYSIOLOGY
Chronic UV light exposure leads to defects in DNA repair that allows for malignant transformation and unchecked growth of tumor cells.
ETIOLOGY
• Basal cell carcinoma:
– Neoplastic transformation of basal cells of epidermis
– Abnormal basal cells proliferate and invade the dermis as nodules or strands
– No premalignant lesion
– Tumor enlargement is usually slow and rarely metastasizes
– Potential to be locally invasive, especially with medial canthal involvement.
– Occur most frequently on lower eyelid followed by medial canthus, upper eyelid, and lateral canthus.
– Distant spread rarely occurs but does so by both hematogenous and lymphatic pathways.
– Classified into 4 groups:
Localized (nodular, nodulo-ulcerative, and cyst): The classic, pearly BCC lesion that is indurated and firm with characteristic telangiectases over the tumor margins. It may display central ulceration. Rarely, a cystic variant is seen.
Diffuse (morpheaform, sclerosing): Flat, firm, white-pink to yellow subcutaneous lesion with indistinct clinical margins. Surface epidermis remains intact, that is, no ulceration. Complete surgical excision difficult and may result in large eyelid defect.
Superficial, multifocal: More irregular surface than nodular BCC and diffuse multicentric involvement of epidermis and dermis.
Fibroepitheliomatous basal cell carcinoma of Pinkus: Usually seen on the trunk.
• Squamous cell carcinoma:
– Arises from prickle-squamous cell layer of epidermis
– Spreads by extension into dermis
– Multiple precursor lesions including actinic keratosis, Bowen’s disease, and radiation dermatoses.
– Occur most frequently on lower eyelid, followed by medial canthus, upper eyelid, and lateral canthus.
– Variable presentation and can be mistaken for basal cell carcinoma.
– Most commonly appear as painless nodular or plaque-like lesions.
– Metastasis to regional lymph nodes but distant spread uncommon.
– Perineural infiltration of SCC of the eyelids allows spread into the orbit, intracranial cavity, and periorbital structures.
• Sebaceous gland carcinoma:
– Arises from the meibomian glands of the upper eyelid or the glands of Zeis.
– Can occur many decades after radiation to the eyelids and face.
– Often presents as small nodules and confused as recurrent chalazia or intractable blepharoconjunctivitis (known as the “masquerader”).
– There are two types of SGC based on the pattern of infiltration and include the nodular and non-nodular type.
– The nodular type is minimally invasive and usually located on the tarsus or eyelid margin.
– The non-nodular type is moderately-to-highly infiltrative and epithelial changes are more common.
– There are also two types of intraepithelial spread and include pagetoid spread and replacement of the full thickness surface epithelium, resembling squamous cell carcinoma in situ.
– Loss of eyelashes in the region of the tumor may help to differentiate SGC from more benign lesions.
– SGC can be multicentric and has true metastatic potential.
– Direct orbital extension into the orbit, paranasal sinuses, and intracranial cavity is possible.
– Spread through lymphatic channels makes regional and systemic metastasis possible.
– Local tumor recurrence after surgical excision is common and frequent surveillance is necessary.
– Medical and oncologic referrals are important.
• Malignant melanoma:
– Neoplastic proliferation of melanocytes.
– Leading cause of death from primary skin tumors.
– Four types including superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma.
– Superficial spreading melanoma of the eyelid is elevated above the skin, has distinct borders, and displays a wide variety of colors including black, tan, rose, or gray.
– Nodular melanoma has spherical nodularity and has a uniform blue–black color.
– Lentigo maligna melanoma arises from a longstanding tan-colored macule and demonstrates surface elevation and nodule formation.
– There are 2 methods to express depth of invasion and these are based on the anatomic level (Clark level) or the depth of invasion in millimeters (Breslow depth). The Breslow depth is the most important of the two classifications.
– Stages I and II have no metastatic disease, stage III has regional lymph node involvement, and stage IV has distant metastasis.
– Initial evaluation should include thorough history and physical, with special attention on the CNS, bone, and GI systems.
– Medical and oncologic referrals are important.
COMMONLY ASSOCIATED CONDITIONS
• The basal cell nevus syndrome (Gorlin-Goltz syndrome) is autosomal dominant with high penetrance.
– Mutation in PTCH gene on chromosome 9.
– Multiple basal cell carcinomas, which can be seen early in childhood.
– Associated with odontogenic cysts of the jaw, skeletal anomalies, and keratinizing pits on the palms and soles.
• Bazex syndrome is an x-linked dominant disorder.
– Multiple basal cell carcinomas that develop on the face in childhood and adolescence.
– Typical “ice-pick marks” on the extremities caused by atrophic dermal changes.
• The linear unilateral basal cell nevus syndrome
– Unilateral distribution of basal cell carcinomas, multiple comedones, epidermoid cysts, and areas of striae-like atrophy.
– Associations with scoliosis and atherosclerotic heart disease.
• Xeroderma pigmentosum is an autosomal recessive disease causing a defect in DNA repair.
– Multiple squamous cell carcinomas, basal cell carcinomas, and melanomas develop on sun-exposed areas and arise in the first 2 decades of life.
• Albinism is an inherited disorder of melanin synthesis.
– Lack of melanin leads to damage by solar radiation and an increased risk for all skin malignancies.
– One-third of all basal cell carcinomas in black Africans occur in patients with albinism.
DIAGNOSIS
• Any patient presenting with an asymptomatic or irritating eyelid lesion should have a prompt biopsy performed by an experienced surgeon (1)[A].
– Incisional biopsy when malignancy suspected, except with malignant melanoma where excisional biopsy with wide surgical margins is preferred.
– Margins of potential sebaceous gland carcinoma and malignant melanoma are sent for permanent section.
– Sentinel node biopsy may be necessary depending on depth of invasion by eyelid melanoma.
• Histopathologic confirmation.
HISTORY
• The following apply for all malignant eyelid tumors:
– Duration
– Slow versus rapid growth
– Previous malignant skin lesion
– History of radiation therapy
– History of arsenic exposure
– History of inflammatory or allergic condition
PHYSICAL EXAM
• Skin ulceration and signs of inflammation
• Distortion/disruption of normal eyelid anatomy
• Abnormal color or texture
• Persistent crusting and/or bleeding
• Focal loss of eyelashes (madarosis)
• Focal whitening of eyelashes (poliosis)
• Presence of abnormal vessels
– Sentinel or feeder vessels
– Telangiectatic vessels at tumor margins
• Orbital signs (proptosis, diplopia, external ophthalmoplegia) are extremely concerning for orbital invasion.
DIAGNOSTIC TESTS & INTERPRETATION
Pathological Findings
• Basal cell carcinoma: Proliferation of cells with oval nuclei and scant cytoplasm. These cells form large nests and have the characteristic “basaloid” appearance. Cells at the periphery of each nest are usually arranged in a radial, or “palisading,” pattern.
• Squamous cell carcinoma: Intraepidermal squamous cell carcinoma is characterized by full-thickness atypia of the epidermis. When the atypical cells invade through the basement membrane, it becomes invasive SCC. Cells are typically polygonal with abundant cytoplasm and dyskeratotic cells with keratin pearls are present.
• Sebaceous gland carcinoma: Numerous sebaceous elements with mitotic figures. Large anaplastic cells are seen with prominent nuclei in foamy or frothy cytoplasm. This foamy appearance is a result of the presence of lipid vacuoles. Highly characteristic is spread of the tumor in the form of infiltrating lobules, nests and cords, as well as superficially.
– Stain positive for lipid with oil red O stain.
• Malignant melanoma: The most common type, superficial spreading melanoma has a radial growth phase characterized by increased numbers of intraepithelial melanocytes that are large and atypical and arranged haphazardly at the dermoepidermal junction. These cells show upward migration (pagetoid spread). Dermal invasion confers metastatic potential.
DIFFERENTIAL DIAGNOSIS
See “Benign Eyelid Neoplasms”.
TREATMENT
• Basal cell carcinoma and squamous cell carcinoma:
– Excision with Mohs micrographic surgery (1)[A] OR
– frozen-section or permanent-section control (1)[A]
– These treatments yield the highest cure rate and lowest recurrence.
– Excise entire tumor with clear margins
– If contraindications to surgery, cryotherapy may be used in a double freeze-thaw method to eradicate the tumor cells (1,2,3)[A]
• Sebaceous gland carcinoma:
– Mohs’ micrographic surgery (1)[A]
– Excision with frozen-section control combined with conjunctival map biopsies (1)[A]
– Some recommend supplemental cryotherapy at the time of excision and topical chemotherapy (mitomycin C) if there is any question of residual involvement (1,6,7)[B]
– If contraindication to surgery, electron beam radiotherapy is an alternative treatment (1,4,5)[B]
– If orbital invasion, exenteration is the preferred treatment (1,6,8)[A]
• Malignant melanoma:
– Recommendations for treatment are varied and often conflicting
– Treatment often depends on Breslow thickness: <1.0 mm- excision with 1.0-cm margins (1)[A], 1.0–2.0 mm- excision with 3.0-cm margins (1)[A]
– Stage III or IV disease: A sentinel node biopsy and lymph node mapping should be performed (1,9,10)[A]
– Stage II-IV disease: Administration of adjuvant interferon should be considered (1,11)[B]
ADDITIONAL TREATMENT
General Measures
Suntan lotion and other protective measures against UV sunlight exposure.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• Ophthalmologist follow-up
– Initially every 1–2 weeks to ensure proper healing of surgical site
– Reevaluation every 6–12 months thereafter, more frequent visits if an aggressive tumor type was identified such as sebaceous gland carcinoma or malignant melanoma.
• Family physician or dermatologist for thorough, full-body, skin examinations.
• Oncology follow-up is important in patients with sebaceous gland carcinoma and malignant melanoma.
• Refer to radiation oncologist if there is need for radiotherapy.
PATIENT EDUCATION
COMPLICATIONS
• Local tissue destruction with loss of normal anatomy and function.
• Orbital, periorbital, intracranial, and systemic spread can occur with any malignant eyelid neoplasm.
• Loss of vision.
• Potentially death if there is intracranial spread or metastasis.
ADDITIONAL READING
• Bartley GB, Garrity JA, Waller RR, et al. Orbital exenteration at the Mayo Clinic: 1967–1986. Ophthalmology 1989;96:468–473.
• Cook BE, Bartley GB. Treatment options and future prospects for the management of eyelid malignancies. Ophthalmology 2001;108:2088–2098.
• Curtis ME, Waltz K. Major review: Basal cell carcinoma of the eyelid and periocular skin. Surv of Ophthalmology 1993;38:169–192.
• Esmaeli B. Sentinel lymph node mapping for patients with cutaneous and conjunctival malignant melanoma [review]. Ophthal Plast Reconstr Surg 2000;16:170–172.
• Gennari R, Bartolomei M, Testori A. Sentinel node localization in primary melanoma: Preoperative dynamic lymphoscintigraphy, intraoperative gamma probe, and vital dye guidance. Surgery 2000;127:19–25.
• Hendley RL, Rieser JC, Cavanagh HD, et al. Primary radiation therapy for meibomian gland carcinoma (case report). Am J Ophthalmology 1979;87:206–209.
• Ide CH, Ridings GR, Yamashita T, Buesseler JA. Radiotherapy of a recurrent adenocarcinoma of the meibomian gland. Arch Ophthalmology 1968;79:540–544.
• Lens MB and Dawes M. Interferon alpha therapy in malignant melanoma: A systematic review of randomized controlled trials. J Clin Oncol 2002;20:1818–1825.
• Lisman RD, Jakobiec FA, Small P. Sebaceous carcinoma of the eyelids. The role of adjunctive cryotherapy in the management of conjunctival pagetoid spread. Ophthalmology 1989;96:1021–1026.
• Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the eyelids; Personal experience with 60 cases. Ophthalmology 2004;111:2151–2157.
• Tuppurainen K. Cryotherapy for eyelid and periocular basal cell carcinomas: Outcome in 166 cases over an 8 year period. Graefes Arch Clin Exp Ophthalmology 1995;223:205–208.
CODES
ICD9
• 172.1 Malignant melanoma of skin of eyelid, including canthus
• 173.1 Other malignant neoplasm of skin of eyelid, including canthus
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