Jacqueline R. Carrasco

BASICS

DESCRIPTION

• The skin of the eyelids includes the epidermis, dermis, and deeper, adnexal tissue.

• The epidermis is comprised of four layers of keratinocytes, as well as Merkel cells, Langerhans cells, and melanocytes.

• The dermis is thicker than the epidermis, containing vessels, nerves, and lymphatics.

• The adnexa lies deep to the dermis and contains holocrine, apocrine, sebaceous, eccrine, and meibomian glands.

• Abnormal growth of any of these structures may fall under the rubric of benign eyelid neoplasms.

• This chapter will focus on the more common neoplasms and provide an overview therein.

EPIDEMIOLOGY

Incidence

• Of all eyelid tumors, 54–84% are benign.

• Incidence of lesions varies widely by study.

• Studies show the most common benign eyelid tumors encountered by the comprehensive ophthalmologist include chalazia and epidermal inclusion cysts.

• Capillary hemangiomas are one of the most common lid tumors in infancy; incidence is approximately 1.0–2.6% of live births.

• The following are data points from a recent review of patients whose neoplasms were surgically removed (1):

• 26% of benign lesions are squamous cell papillomas.

• 21% of benign lesions are seborrheic keratosis. Other studies note their ubiquitous nature amongst the elderly, citing that 80–100% of people older than 50 have them.

• Melanocytic nevi, hidrocystomas, and xanthoma/xanthelasma are the next most common benign eyelid tumors.

• Premalignant lesions such as actinic keratosis, Bowen disease, and keratoacanthomas are beyond the scope of this chapter and will not be further discussed.

Prevalence

• Eyelid tumors are the most common neoplasm encountered in a general ophthalmology practice.

• Overall prevalence depends on tumor type.

RISK FACTORS

• Meibomian gland inspissation and ocular rosacea may lead to chalazia and hordeolum formation.

• Female gender is a risk factor for capillary hemangiomas (3:1 female:male ratio).

• Eyelid trauma is a risk factor for epidermoid cysts.

• Eyelid surgery and infection are risk factors for inflammatory lesions and cysts.

• HPV (human papilloma virus) is a risk factor for squamous cell papillomas (particularly those in the oral mucosa).

• Sun exposure, equatorial origin, and advanced age predispose to lesions such as actinic keratosis and keratoacanthomas. Moreover, they are risk factors for progression to malignancy.

• Hypercholesterolemia and familial lipid disorders predispose to xanthelasma/xanthoma.

Genetics

It depends on lesion involved and is beyond the scope of the overview provided in this chapter.

GENERAL PREVENTION

• Limitation of ultraviolet ray and sun exposure as well as sunscreen use are perhaps the most important means of prophylaxis against the development of UV ray-associated eyelid neoplasms.

• Lid hygiene may reduce occurrences of chalazia and various cysts.

• Improved lipid metabolism may prevent and/or treat xanthoma formation.

PATHOPHYSIOLOGY

• Chalazion: Retained sebaceous secretions

• Epidermal inclusion cyst: Epidermis implanted in the dermis, usually from trauma or surgery

• Capillary hemangioma: Hamartomatous proliferation of benign vascular endothelium, likely of placental origin

• Squamous cell papilloma: Benign epithelial tumor

• Seborrheic keratosis: Originating in keratinocytes with acanthosis from basaloid cell proliferation. Somatic fibroblast growth factor receptor 3 mutations and activating transmembrane tyrosine kinase receptor mutations have been identified.

• Melanocytic nevus: Clumps of neural-crest derived melanocytes that migrate to the dermis and epidermis during development

• Xanthoma/Xanthelasma: Concentration of lipocytes

ETIOLOGY

• Chalazion: A chronic lipogranulomatous inflammatory lesion that is sterile. It may affect the meibomian glands, the glands of Zeis, or both. When superinfected, termed a hordeolum.

• Epidermal inclusion cyst: A superficial epidermal round keratin-filled lesion.

• Capillary hemangioma: A pink to faint red to violaceous macular lesion composed of vascular channels surrounded by a white halo. They typically undergo three stages: A proliferative phase, a stable period, and then involution. See the Treatment section.

• Squamous cell papilloma: Pedunculated “finger-like” projections often compared to fibroepithelial polyps found elsewhere on the body.

• Seborrheic keratosis: Usually multiple gray-brown greasy, scaly, sharply demarcated papules/plaques that may appear anywhere on the body except the palms and soles, with a predilection for the face and upper torso/back.

• Melanocytic nevi: Typically a flat lesion, ranging from smooth to verrucous, from well demarcated to slightly irregular, and from deeply pigmented to light (amelanotic).

• Apocrine hidrocystoma: Involving the glands of Moll, cysts and nodules can also involve any gland (Zeis, sweat, meibomian) of the eyelids. Pathology and histology depend on subtype.

• Xanthoma/xanthelasma: Yellow subcutaneous papules or plaques usually on the nasal upper eyelids. May also occur at lateral canthi.

COMMONLY ASSOCIATED CONDITIONS

• Ocular rosacea may be associated with chalazion and hordeolum formation.

• Visceral hemangiomas may be associated with multiple cutaneous capillary hemangiomas. Large hemangiomas may be associated with high-output cardiac failure or Kasabach–Merritt syndrome (thrombocytopenia, anemia, and low coagulant levels). Rarely, Maffucci syndrome, which has involvement of the feet and long bones, may be associated.

• Seborrheic keratoses may be associated with internal malignancies and may serve as cutaneous markers thereof.

• Dysplastic nevus syndrome, when multiple dysplastic nevi occur, is associated with increased risk of cutaneous/conjunctival/uveal melanomas.

• Corneal arcus in young age group, in the presence of xanthelasma, may signify hypercholesterolemia.

• Muir–Torre syndrome, Gorlin–Goltz syndrome, and xeroderma pigmentosum are syndromes associated with systemic malignancies/malformations but are associated with malignant skin tumors and will not be further discussed.

DIAGNOSIS

HISTORY

• Close attention should be paid to the duration of the lesion and to the pace of its growth, as noninflammatory benign lesions are typically slow growing or do not grow at all.

• Bleeding and necrosis are warning signs, as feeder blood vessels and tumors outgrowing their blood supply may signify malignancy.

• Previous history of skin lesions, benign or malignant, similar to or different from current pathology may provide insight into etiology of lesion or associations thereof.

• History of ocular surgery or trauma should be noted.

• History of systemic malignancies may be related.

• Previous treatment of inflammatory conditions such as allergies or blepharitis. These may predispose to eyelid cysts or chalazia. Unfortunately, chronic, unilateral blepharitis may be a misdiagnosis for a potentially malignant underlying etiology (e.g., sebaceous cell carcinoma).

• History of blistering sunburns, chronic UV exposure, and proximity to equator must be investigated.

• Previous history of radiation therapy should be taken into account.

PHYSICAL EXAM

• Thorough examination of the eyelids, including lid-flipping to examine tarsal conjunctiva, and adnexa for additional lesions, should be performed.

• Preauricular, submaxillary, cervical lymph nodes must be palpated.

• Lesions themselves must be inspected for ulcerations, necrosis, and neovascularization, all potential warning signs.

• Skin changes overlying the tumor itself are important in narrowing the differential diagnosis.

• Bleeding and discharge should be noted.

• Madarosis (loss of eyelashes), poliosis (whitening of eyelashes), and meibomian gland destruction should be noted, both locally and remote from lid lesions.

• Thorough slit-lamp and fundus examination should be performed in all patients.

• Capillary hemangiomas must be frequently monitored for facial distortion, interference with physiologic functioning (respiration, swallowing, hearing), strabismus, amblyopia, and bleeding.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Any discharge may be sent for culture.

• Systemic laboratory tests are unnecessary unless malignancy or systemic involvement/associations are suspected.

Imaging

Imaging for benign eyelid lesions is unnecessary unless malignancy or systemic/orbital involvement is suspected.

Pathological Findings

• Chalazion: Inflammatory reaction composed primarily of epithelial, lymphocytic, and plasma cells with neutrophils and eosinophils on occasion.

• Epidermal inclusion cyst: Cavity lined by stratified squamous epithelium within the deeper dermis, filled with keratin.

• Capillary hemangioma: Nonencapsulated vascular channels of varying size in the dermis and subcutaneous tissue.

• Squamous cell papilloma: Vascular connective tissue encased by acanthotic, hyperkeratotic, and parakeratotic epithelium.

• Seborrheic keratosis: At least 6 variants, including acanthotic, reticulated, hyperkeratotic, clonal, inflamed, and melanoacanthoma subtypes. Histopathology depends on subtype.

• Melanocytic nevi: May be junctional, compound, or intradermal, with diagnosis being made by nest-like cellular arrangement.

• Xanthoma/xanthelasma: Dermal lipid-laden histiocytes with or without giant cells.

TREATMENT

Organized by Lesion Etiology

Chalazia:

First line

• Warm compresses with light massage at least q.i.d. for 10 min each time, with lid hygiene, are useful.

• Topical ophthalmic antibiotic is used for draining lesions or associated blepharitis.

Second line

• Incision and curettage are required.

• Steroid injection, dosage of which may depend on size of lesion, may be used. Triamcinolone can lead to depigmentation and skin atrophy.

• Oral doxycycline (100 mg PO b.i.d.) may be considered, particularly if associated with ocular rosacea.

Cysts:

First line

• Marsupialization, whereby the top of the lesion is amputated and contents are allowed to drain with secondary epithelialization, is required to be performed.

• Complete excision of the entire lesion in an attempt to keep capsule intact is required.

Second line

• Oftentimes complete excision follows failed marsupialization (rare).

• Nonsurgical modalities including injection of trichloroacetic acid have been shown to be useful for large or confluent apocrine hydrocystomas.

Capillary Hemangiomas:

First line

• 50% of lesions regress within 5 years, and 70% within 7 years. They often continue to fade into the early teens. Oftentimes frequent observation is warranted as a result.

• Therapy is undertaken for aggressive lesions as described above and is often individualized.

• Oral steroids at 2–4 mg/kg per day may be indicated for rapidly growing or distorting lesions.

Second line

• If the visual axis is involved, intralesional triamcinolone or betamethasone acetate may be administered (side effects include skin necrosis, adrenal suppression, growth retardation, and retinal artery occlusion).

• Interferon alpha-2a may be injected in refractory and particularly aggressive cases.

• Vascular-specific pulsed dye lasers can be effective in promoting involution of smaller lesions.

• Recently, propranolol has been administered for progressive lesions. Dose is usually 1 mg/kg per day in 3 equal doses for 1 week, doubled after 1 week, then tapered as seen fit. Typically propranolol is monitored in conjunction with child’s pediatrician. See the ‘Hemangioma in children’ chapter.

Xanthelasma/Xanthoma:

First line

• Laser ablation or surgical excision is required.

Second line

• Oral simvastatin has recently been shown to resolve xanthelasma in association with lowered systemic lipid levels (2).

Papillomas/Seborrheic Keratosis/Nevi:

First line

• Treatment remains optional and cosmetic for all clinically benign lesions. However, lesions can grow and cause irritation and/or bleeding which necessitate excision.

• For cosmetic removal, laser ablation and cryotherapy are viable first-line options.

• Surgical excision of lesion, with wide margins entailing small portions of surrounding normal tissue, is required.

Second line

• For any suspicious lesion, biopsy must be performed.

• Incisional biopsies are common.

• Excisional biopsy with wide margins is preferable, and margins should be sent for both permanent and frozen sections.

• Mohs’ micrographic surgery is an alternative intraoperative technique to ensure full resection in alternative to frozen sections.

• Map biopsy may be performed if diffuse local involvement is seen or suspected.

• Sentinel node biopsy may be indicated.

ADDITIONAL TREATMENT

General Measures

Reserved for malignant lesions: Include radiotherapy and/or chemotherapy. These are outside the scope of this chapter.

Issues for Referral

• Babies being treated for aggressive hemangiomas should be done so with consult to pediatric endocrinology, general pediatrics, and pediatric cardiology depending on treatment.

• Xanthoma/xanthelasma patients, particularly young (<50 years), may warrant referral to internists for evaluation of hyperlipidemia.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

Neonates on propranolol for hemangiomas require vital sign checks every 30 min for 4 h after beginning the treatment. This should be done in collaboration with pediatric cardiology (3).

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• All treated lesions should be followed chronically for recurrence. Care must be taken to differentiate recurrence from incomplete excision in surgical cases, as recurrences may involve different, potentially malignant pathology.

• Neonates with capillary hemangiomas should be examined twice weekly for 2 weeks after discharge, and then weekly by their internist. Ophthalmic evaluation frequency is subjective, but may be monthly to monitor aggressively for amblyopia (3).

• Care of premalignant and malignant lesions is outside the scope of this chapter.

DIET

Low cholesterol diet encouraged in patients with xanthomas/xanthelasmas

PATIENT EDUCATION

Specific to associations and risk factors as above

PROGNOSIS

Good for all benign lesions

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