Continuing Education Activity

Benign eyelid lesions can be inflammatory, infectious, traumatic, or neoplastic in origin. They are a common condition that requires differentiation from malignant and pre-malignant lesions. Management options include observation, biopsy, excision, injection with steroids, topical application of steroids, antibiotics, antimicrobials, oral antibiotics, application of warm compresses, and cleaning of the eyelid margins. This activity reviews the evaluation and treatment of benign eyelid lesions and highlights the differential diagnosis as well as surgical and non-surgical treatment.

Objectives:

• Distinguish benign from pre-malignant and malignant eyelid lesions.
• Describe the clinical presentation of benign eyelid lesions.
• Review the eyelid structures that can give rise to benign eyelid lesions.
• Outline the management of different benign eyelid lesions.

Introduction

Benign eyelid lesions are commonly found during a routine exam by the eye care provider, primary care provider, or dermatologist. The most common benign inflammatory lesions include chalazion and pyogenic granuloma.   Infectious lesions include verruca vulgaris, molluscum contagiosum, and hordeolum. Benign neoplastic lesions include squamous cell papilloma, epidermal inclusion cyst, dermoid/epidermoid cyst, acquired melanocytic nevus, seborrheic keratosis, hidrocystoma, cyst of Zeiss, and xanthelasma.[1][2][3] 

Many less common lesions can mimic the more common ones. All benign lesions need to be differentiated from pre-malignant lesions that include actinic keratosis and keratoacanthoma, as well as malignant lesions that include basal cell carcinoma, squamous cell carcinoma, sebaceous carcinoma, Merkel cell carcinoma, metastatic lesions, cutaneous lymphoma, and melanoma.[4][5][6][7][8] 

A careful history that includes questions regarding predisposing factors, duration, and rate of growth of the lesion, symptoms of tenderness, discharge, or bleeding, combined with careful clinical observation, will determine whether to observe the lesion or refer for a biopsy and histopathological analysis.[9] 

When indicated, treatment consists of excision, curettage, electrocautery, cryosurgery, or different types of laser treatments.

Most benign lesions originate from the epidermis, dermis, or adnexal structures of the skin (meibomian glands or glands of Moll and Zeiss). In several studies, about 80 to 85% of eyelid lesions that required biopsy were benign.[10][11]

Etiology

The etiology of benign eyelid lesions is best differentiated according to the tissue from which the lesion originates.[12] The eyelid comprises four to seven layers depending on the zone of the eyelid and lower or upper eyelid. Each of these layers can give rise to benign lesions. The lower eyelid has a zone located at the lid margin and is 5 mm wide, and a distal zone, also 5 mm wide, adjoins the orbital rim. The upper eyelid has a 5 mm zone at the eyelid margin, a middle zone of 5 mm, and a 10 mm distal zone that adjoins the orbital rim and eyebrow. The tissue distribution is as follows:

• Skin, subcutaneous tissue, and adnexa (upper and lower lids, all sections of lids) 
• Orbicularis muscle (upper and lower lids, all sections of lids)
• Pre-aponeurotic orbital fat (upper lid, distal portion)
• Pre-capsulopalpebral fascial fat (lower lid, distal portion)
• Levator aponeurosis (upper lid, middle and distal portion)
• Capsulopalpebral fascia (lower eyelid distal portion)
• Müller muscle (upper/margin/distal)
• Tarsus with the meibomian glands (upper and lower lids, all sections of lids)
• Palpebral conjunctiva (upper and lower lids, all sections of lids)

Adnexal structures in the eyelid skin include eyelashes, sebaceous glands of Zeis, and sweat glands of Moll. The levator and orbicularis muscles are made up of striated muscle, while Müller's muscle is made up of smooth muscle. The marginal part of the orbicularis muscle is called the muscle of Riolan, and the superficial part of this muscle can be observed as a colored line that separates the meibomian gland orifices from the row of eyelashes. This line is called the gray line and is significant as it demarcates the separation of the anterior and posterior lamellae. Lesions in front of the septum are called preseptal and, as in the case of preseptal cellulitis, are less serious than those posterior to the septum, such as orbital cellulitis.  

The most common causes of benign eyelid lesions are:

• Inflammation of a blocked gland (e.g., chalazion)
• Infection and inflammation of a gland (e.g., hordeolum)
• Lipid accumulation in the dermis (e.g., xanthelasma)
• Cyst formation of adnexal or epidermis structures (e.g., epidermal inclusion cyst, cyst of Moll, cyst of Zeiss)
• Melanocyte proliferation in the dermis and epidermis (e.g., nevus)
• The proliferation of cells in the epidermis (acanthosis) and hyperkeratosis (e.g., seborrheic keratosis, acrochordon/skin tag)
• Infection of the epidermis (usually viral, e.g., verruca vulgaris, molluscum contagiosum)[12][4]

Several of the phakomatoses are associated with benign eyelid lesions.[13][14][15] These include:

• Neurofibromatosis Type 1 -plexiform neurofibroma
• Tuberous sclerosis -angiofibroma
• Sturge-Weber Syndrome -port-wine stain

Epidemiology

In one study of 408 patients, the following eyelid lesions in order of frequency were: chalazion (28%), squamous papilloma (11%), epidermal inclusion cyst (7%), seborrheic keratosis (5%), xanthelasma (5%), cysts of Moll and Zeiss (5%), nevus (4%), verruca vulgaris (3%), dermoid/epidermoid cyst (3%), capillary hemangioma (2%), keratoacanthoma (1%), cutaneous horn (1%), xanthogranuloma (<1%), trichoepithelioma (<1%), apocrine hidrocystoma (<1%.[7]

In another large study of 2639 eyelid lesions, the most common benign eyelid lesions were inflammatory (chalazion), melanocytic nevus, squamous papilloma, dermoid cyst, and epidermal inclusion cyst.

Skin

Epidermis

• Seborrheic keratosis (SK) is one of the most common benign lesions of the eyelid, with increasing prevalence over the age of 50 years. Associated with a predisposing mutation in FGFR3. This mutation is more common in sun-exposed skin, and therefore sun exposure, as well as a family history of SK, are associated with the development of SK. The sudden appearance of multiple seborrheic skin lesions is called the Leser-Trélat sign and is associated with gastrointestinal adenocarcinoma.[16]
• Dermatosis papulosa nigra (DPN).  Most common in Black race individuals s as well as Asians and correlated with the level of skin pigmentation. One study found that one-third of Blacks have DPN lesions. It is considered a variant of SK. However, unlike SK, it commonly develops in the 2nd decade. It is more likely in women, and there is a strong familial predisposition. Like SK, it is associated with a mutation in FGFR3.
• Inverted follicular keratosis is an uncommon lesion in patients over age 60 and is associated with sun exposure.[17]
• Verruca vulgaris or common wart affects about 10 percent of the world population and is more common in the first and second decade of life, with up to 20 percent affected in this age group. They are more common in Whites, immunosuppressed patients, and meat handlers. Warts are spread through skin-to-skin contact, and behaviors and practices within certain populations (such as children) affect the prevalence.[4]
• Molluscum contagiosum has an average worldwide prevalence of 0.8 percent. It is most common in pre-school-age children. In adults, it is most common in immunocompromised individuals. There is no racial, geographic, or sex predilection.[7]
• Squamous papilloma (acrochordon or skin tag). Most common benign eyelid lesion of epithelial origin. More common in middle age to older patients.[18]
• Epidermal inclusion cysts. Congenital or acquired. The acquired form is the most common benign skin lesion and occurs due to localized skin trauma from a rash, chemicals, or sun exposure.[19]
• Cutaneous dermoid cyst. Most are congenital and found in the first two decades of life.[20]
• Keratoacanthoma. Most common between 50 and 69 years of age with a male to female ratio of 2 to 1. More common in lightly pigmented individuals.[21]
• A cutaneous horn is most common in individuals 60 to 80 years of age. Cutaneous horn may be pre-malignant or benign. Individuals with benign lesions are an average of 9 years younger than those with pre-malignant lesions. Pre-malignant lesions are more common in males.  Benign lesions have no sex predilection.[22]

Melanocytic

• Ephelis (freckles) are most common in individuals with very light skin types and blond or red hair. They tend to be inherited in an autosomal dominant manner and become darker when exposed to sunlight.[23]
• Lentigo simplex is the most common type of lentigo, present at birth and not affected by sunlight. Incidence and epidemiology are not well studied.[24]
• Solar lentigo correlates with sun and UV light exposure. In Whites in the United States, solar lentigo is observed in 90 percent over 60 and only 20 percent under 35 years of age.[24]
• Nevi of all types are found in Blacks, Whites, and Asians alike. Nevi become more common with age. Nevus acquisition increases most during pre-teen and teenage years and is correlated with sun exposure. In one study, nevi were found to be present in 60 percent of adults in a predominantly white population. Acral nevi (on the palms and soles) are more prevalent in Blacks and Asians.[25]
  • Congenital eyelid nevi
    • Split nevus, where the nevus is present on both the upper and lower eyelid, is rare, and around 30 cases have been reported worldwide.[26]
    • Oculodermal melanocytosis (ODM, nevus of Ota): One large study determined a prevalence of 0.038% in Whites and a 0.014% prevalence in Blacks. Another study determined that the lifetime risk of uveal melanoma in patients with ODM is 0.25%.[27][28]
    • Giant hairy pigmented nevi are uncommon congenital nevi and are estimated to be present in less than one in 20,000 newborns. A Mongolian spot is an uncommon congenital nevus that is more common in Asians, Blacks, Native Americans, and Hispanics. Both can be present on the face.[29][30]
    • Blue nevi have a 2 to 1 female to male predilection. The prevalence is 3 to 5% in Asians, compared to 1 to 2% in Whites.[31]
  • Acquired nevi
    • Spitz and Reed nevi are uncommon and occur in less than 0.01 percent of the population. 70 Percent develop before age 20 and are associated with lighter skin types.[32]
    • Melanocytic nevi (Junctional, Intradermal, Compound) are present in about 60% of the population. Junctional nevi tend to progress to compound and then to intradermal with age. Due to this, junctional nevi are more common in the pediatric population and intradermal more common in the aging population.
    • Dysplastic nevi are present in 2 to 18% of the population.

Adnexal Lesions: Lesions that do not arise from the skin are called adnexal lesions and arise from hair follicles, sweat glands, sebaceous glands, and accessory lacrimal glands. 

• An external hordeolum is a blocked and infected gland of Moll, Zeis, or eyelash follicle. As such, it is an adnexal eyelid lesion. External hordeola are a common eyelid lesion without a sex or race predilection. It is more common in adults but can occur in children. It is more common in patients with blepharitis, meibomian gland dysfunction, acne rosacea, and those who have had chalazia or hordeola in the past.[33]

Hair Follicles

• Trichoepithelioma is a very rare lesion with three subtypes, two of which are inherited in an autosomal dominant fashion with increased penetrance in females (multiple familial and desmoplastic trichoepithelioma) and one (solitary trichoepithelioma) not inherited.[34]
• Trichofolliculoma is rare, more common in adults, and possibly more common in males.[35]
• Trichilemmoma is relatively common, with an estimated 1 in 2,500 skin biopsy samples in pathology laboratories in the United States testing positive for this lesion. It is more common in Whites and, in the case of Bowen disease, more common in females.[36]
• Pilomatrixoma is more common in the first two decades of life and a relatively common finding among skin biopsy samples in the United States and globally.[37]

Sweat Glands

• Apocrine hidrocystoma (cyst of Moll): Does not have a sex or race predilection and is one of the most common eyelid lesions encountered. It is more common in adults.[38]
• Eccrine hydrocystoma: This is not a common eyelid lesion. It is also more common in adults.[38]
• Trichilemmal (pilar) cysts are common and occur in about 10% of the population. They occur in younger and female individuals without a known racial predilection. In some cases, an autosomal dominant inheritance is present.[39]
• Syringoma is an uncommon eyelid lesion that occurs in 1% of the population. They are more common in females and occur during puberty and increase in number with aging.[40]
• Pleomorphic adenoma is more common in the lacrimal gland but can also grow in the eyelid. In the eyelid, it is rare, making up about 0.01% of all benign adnexal tumors. It is more common in middle-aged men.[41]
• Eccrine spiradenoma is a rare eyelid lesion of persons aged 15 to 35 years. No sex or racial predilection is known.[42]

Accessory lacrimal glands are located at the conjunctival fornix (glands of Krausse), the distal edge of the tarsal plate (glands of Wolffring), and within the caruncle (glands of Popov). In one study of 27 patients with accessory lacrimal gland tumors, the mean age was 56 years, a slight male predominance was found (1.4:1), and 89% of lesions were found to be pleomorphic adenoma, 7% adenoid cystic carcinoma, and 4% oncocytoma. Of these, pleomorphic adenoma and oncocytoma are benign lesions. Both lesions are rare.[43]

Sebaceous Glands

• Chalazion and internal hordeolum are some of the most common benign eyelid lesions found. In one study, 1% of all new patients presented for a chalazion or internal hordeolum. This study found no sex predilection, and chalazia are most common in the third decade of life, and 10% of chalazia recurred.[44][45]
• Cyst of Zeis is one of the most common benign lesions of the eyelid. It becomes more common with age.[46]
• A sebaceous cyst (steatocystoma) is an uncommon eyelid lesion as it develops from ordinary sebaceous glands and not the ones associated with the eyelashes. It can be associated with steatocystoma multiplex, a rare autosomal dominant inherited disorder of the sebaceous glands.[47] 
• Sebaceous gland hyperplasia is more common in the over 60-year-old population.[48]
• Sebaceous gland adenoma is more common in the over 60-year-old population. The practitioner should suspect Muir–Torre syndrome in younger patients, especially when multiple adenomas are present.

Stromal Lesions

Xanthelasma: More common in middle age and older. One-third of patients have hyperlipidemia.[49]

Vascular Lesions          

• Pyogenic granuloma is associated with tissue disruption from surgery or injury to the tarsal plate from a chalazion. In one study of conjunctival biopsies, pyogenic granuloma was reported to be the most common lesion. In this study, the average age was 27 years. Pyogenic granulomas can be found in all mucous membranes and the skin. Pyogenic granulomas, in general, are most common in the 2nd and 3rd decades of life.[50]
• Capillary hemangioma is one of the most common benign childhood orbital lesions and affects 1 to 5% of infants under the age of 1 year. There is a 3 to 1 female to male predilection.[51]
• Cutaneous angiofibroma is associated with tuberous sclerosis and multiple endocrine neoplasia type 1 and Birt-Hogg-Dube syndrome and is strictly found in this population. In the case of tuberous sclerosis, angiofibromas will start to develop in the first decade of life and continue developing into the second decade.[13]
• Nevus flammeus (port-wine stain) is a common congenital eyelid lesion that affects 0.3 to 0.5% of newborns. No gender predilection has been noted. It is strongly associated with Sturge Weber Syndrome; however, only 6% of babies born with a nevus flammeus develop Sturge Weber syndrome.[52]

Neurogenic

• Plexiform neurofibroma is associated with neurofibromatosis type I (NF1), which has an incidence of 1 in 30,000. NF1 is inherited in an autosomal dominant fashion; however, about half of all cases are from de novo mutations and are not inherited. Plexiform neurofibromas occur in about 10% of patients with NF1 and can involve the eyelid, orbit, periorbital and facial structures.[53]
• Solitary neurofibroma is the most common tumor of the peripheral nerve sheath. It has no racial or sex predilection and, while occurring in all ages, is more common in the 20 to 40 age group.[54]
• Schwannomas are most common in the 50 to 60-year-old age group. There is no sex or racial predilection. The incidence is about 5 cases per 100,000 adults/year adults and about 0.4 cases per 100,000/year in children. Vestibular schwannomas are most common, followed by the upper limbs and the head. Schwannoma of the eyelid is rare.[55]

Lipomatous

• Lipomas occur in 1% of the population with a slightly higher preponderance in males and are more common in the 40 to 60-year-old age group. Eyelid lipomas are uncommon.[56] 

Pathophysiology

Skin

Epidermis

• Seborrheic keratosis (SK) appears as a greasy, "stuck on" lesion with different degrees of pigmentation. The surface can be rough and wart-like in appearance. More common in UV exposed skin. Hallmarks of these lesions that are observable with the slit lamp are (1) milia-like cysts, (2) comedo-like openings, and (3) fissures and ridges.[16]
• Dermatosis papulosa nigra (DPN).  DPN lesions appear in the 2nd decade of life as small round macules of variable pigmentation localized mainly on the cheeks, forehead, temples, and eyelids. Over time the lesions grow darker and larger (with elevation up to 3 mm and size up to 5 mm) and number. The lesions do not bleed or crust.[57]
• Inverted follicular keratosis. A solitary papillary or nodular lesion that is keratotic and may have pigmentation, usually at the margin of the upper eyelid. It often looks similar to squamous cell carcinoma.[17]
• Verruca vulgaris appears as a discrete elevated papillomatous, hyperkeratotic, and acanthotic lesion often on the eyelid margin, is non-pigmented and may have a digitated surface. Of the many types of warts, the filiform type tends to cause warts on the eyelids and face. This type is caused by human papillomavirus (HPV), and in the case of filiform warts, pronounced elongated papillomatous projections are present.[58]
• Molluscum contagiosum lesions are firm, 1 to 10 mm in size, pearly to flesh-colored, dome-shaped lesions with a central umbilication that often contains a central core containing live viral particles. When lesions are close to the ocular surface, chronic follicular conjunctivitis can result from viral shedding.[59]
• Squamous papilloma (acrochordon or skin tag) - This is a lesion often with a stalk and keratinized surface that appears polypoid and is generally not solitary. It occurs more frequently in areas where skin layers rub against each other (e.g., eyelids, groin, armpits, neck). When the stalk is twisted, the lesion may infarct, which will cause a darkening of the lesion.
• Epidermal inclusion cysts/milia. An elevated, lightly colored, smooth lesion exhibiting slow growth with a central pore. Small cysts that are 1 to 2 mm are called milia.[60]
• Cutaneous dermoid cyst. Usually solitary and on the forehead or, when on the eyelids, usually closer to the eyebrow. The average size is 10 to 40 mm, and the lesion may not move freely as it is often attached to the periosteum.[20]
• Keratoacanthoma originates at the base of the lashes or other hair on the eyelid in the upper portion of the hair follicle (infundibulum). It is a fast-growing nodule with a central keratin plug surrounded by rolled margins. The lesion grows rapidly for 6 to 8 weeks, followed by weeks to months of no growth and stable appearance. The lesion often will involute leaving a scar.[21]
• Cutaneous horn describes a hyperkeratotic well-circumscribed lesion that is at least twice as high as it is wide at the base of the lesion. Current categorization is based on the underlying cause. On the eyelid, possible causes are epidermoid cyst, squamous cell carcinoma, verruca vulgaris, and others. Underlying benign lesions tend to be associated with slower growth, with the final size attained in months to years. Faster growth rate and pain are associated with underlying malignancy.[22]

Melanocytic

• Ephelis (freckles) is a small, uniformly pigmented, well-circumscribed macular lesion present on sun-exposed areas, including the eyelids or conjunctiva. Ephelides develop in early childhood and will reversibly increase in size, number, and level of pigmentation based on the degree of sun exposure.[23]
• Lentigo simplex is a small, brown, or black, flat lesion that appears similar to a junctional nevus. It is not affected by exposure to sunlight and is not more prevalent in sun-exposed areas.[24]
• Solar lentigo is a lesion of variable size, light to dark brown, that develops over time in sun-exposed areas of the body. This lesion is also called "sunspots," "liver spots," or "age spots."
• Nevi[61][62][63] 
  • Congenital
    • Split nevus (also known as a "kissing nevus") is a compound nevus located on the upper and lower eyelid.[26]
    • Oculodermal melanocytosis (ODM, nevus of Ota) is a flat, blue-to-gray, lesion of the eyelid and periorbital skin and a change of the color of the sclera to blue. It is almost always unilateral.[27]
    • Giant hairy pigmented nevus is a flat dark nevus, often covered with hair, that appears in childhood. It will keep growing until it is 40 cm or larger. It can be on the face but is usually on the trunk.[30]
    • Mongolian spot nevus present at birth or soon after, 2 to 8 cm in size, flat, blue to blue-gray, with irregular, poorly distinguished edges, can be on the face but usually on the trunk.[64]
    • Blue nevus is dark blue, smooth, dome-shaped, and round. The common blue nevus is smaller, and the cellular blue nevus is larger than 1 cm.
  •   Acquired
    • Spitz: pink and dome-shaped, grows rapidly, with onset during the first two decades. More likely on the face, neck, or legs. Lesions can be other colors, including red, blue, tan, or brown.[32]
    • Reed: a variant of a Spitz nevus that is black with feathered edges.
    • Melanocytic nevus
      • Junctional: 1 to 10 mm flat or slightly elevated, round or oval macule with a uniform medium to dark brown pigmentation.
      • Intradermal: 5 to 10 mm, elevated (round, dome-shaped, or pedunculated), non-pigmented (skin-colored), may have hair. May grow from an existing nevus.
      • Compound: 1 to 10 mm, displaying a symmetrical central raised area surrounded by a flat area, with variable pigmentation that is symmetrically distributed.
      • Dysplastic: Often larger than 6 mm, with a darker pigmentation pattern in the center ("fried egg" appearance). Often fits other criteria for concern of malignancy, including irregular borders and asymmetry.

Adnexal Lesions  

• External hordeolum is a painful lesion at the base of an eyelash associated with inflammation. It presents as a painful, warm, swollen, red eyelid abscess that can have a pus point. When it does, this is called a "pointing" hordeolum.[44][33]

Hair Follicles

• Trichoepithelioma is a lesion that originates from hair follicles in sun-exposed areas on the face and scalp. It presents as multiple (in the inherited form) or single (in the sporadic form) skin-colored lesions 2 to 8 mm in size.[34]
• Trichofolliculoma resembles a sebaceous cyst, often with a central umbilication that contains white hair.[35]
• Trichilemmoma resembles verruca or BCC and consists of smooth and well-defined papules or verrucous growths that may be solitary or multiple.[36]
• Pilomatrixoma presents as a solitary, subcutaneous, pink to a purple, painless, firm nodule that grows over months to years. It is normally 15 to 30 mm in size, but much larger lesions of up to 15 cm have been reported. It is more often found in the upper eyelid or eyebrow and can resemble a chalazion. It often contains a calcified center.[37]

Sweat Glands

• Apocrine hidrocystoma (cyst of Moll) is a type of sudoriferous cyst of the sweat gland at the base of an eyelash. It develops most often on the inner canthus as a clear papule or nodule of usually 1 to 3 mm but can be up to 15 mm in size, with the color varying from flesh color to blue or black. This lesion often looks tense and shiny with edges that blend into the skin. The lesion transilluminates. It does not easily rupture or involute. It is not affected by variations in temperature.[38]
• Eccrine hydrocystoma is a type of sudoriferous cyst of the sweat glands of the skin. It is a slow-growing clear cyst that does not disappear and averages 4 to 10 mm in size. It is usually on the nasal or temporal side of the eyelid close to (but not on) the eyelid margin. It is affected by temperature.[38]
• Trichilemmal (pilar) cysts commonly present as flesh-colored nodules that are well-circumscribed, firm, smooth, and mobile, ranging in size from 5 mm to as large as 50 mm.[39]
• Syringomas are yellow to skin-colored papules that are usually 3 mm or smaller in size and are usually limited to the lower lids.[40]  
• Pleomorphic adenoma presents as a slow-growing subdermal mass of 2-6 cm in size.[41]
• Eccrine spiradenoma is a flesh-colored, gray, pink, purple, red, or blue nodule about 10 mm in size that is soft and can be tender to palpation.[42]

Accessory Lacrimal Glands 

• Pleomorphic adenoma presents as a painless, slow-growing deep eyelid lesion that mimics a chalazion.[43]
• Oncocytoma also presents as a painless, slow-growing deep eyelid lesion that mimics a chalazion except when on the caruncle, where it appears as a fleshy growth.

Sebaceous Glands

• A chalazion can present as a deep chalazion in the meibomian glands or a superficial one in the gland of Zeis. It is a painless, slow-growing nodule that may persist for months and become chronic. It can break through the tarsal plate and present as a lesion of the anterior portion of the eyelid. A chalazion of the gland of Zeis is usually located at the eyelid margin.
• Internal hordeolum (Meibomian gland) presents as a deeper, painful elevated lesion, usually more visible on the conjunctival side of the eyelid. A pus point may be present.[46]
• Cysts of Zeis develop as a solitary lesion at the base of an eyelash. They are filled with yellow/turbid material and do not transilluminate. 
• Sebaceous cysts (steatocystoma) develop as solitary lesions, usually at the nasal canthus. They are filled with yellow/turbid material and do not transilluminate. It is of note that sebaceous cysts, epidermal inclusion cysts, and pilar cysts are often confused. The latter two contain keratin and not sebum.[47]
• Sebaceous gland hyperplasia presents as a yellow, elevated, soft nodule that generally displays umbilication.[48]
• Sebaceous gland adenoma presents similar to sebaceous gland hyperplasia. Histopathology is used to differentiate hyperplasia from adenoma and carcinoma.

Stromal Lesions

Xanthelasma: Slightly elevated, usually bilateral, yellowish, lightly colored lesion located at the upper or lower medial canthus.[65]

Vascular Lesions          

• Pyogenic granuloma appears as a fleshy, pink to red, vascularized, and lobulated lesion found on the tarsal conjunctiva. It tends to form as a sequela to a chalazion after eyelid surgery or in the presence of an irritating foreign body such as a suture. It can grow large enough to be visible past the eyelid margin, or it may only be observed after the eyelid is everted.[50]
• Capillary hemangiomas are usually found within the first year of life and present as a cutaneous, subcutaneous, or orbital lesion. Lesions will grow, become deeper red and become lobulated during the first year of life. Cutaneous lesions appear red, subcutaneous blue or purple, and orbital lesions can cause proptosis, strabismus, and optic nerve compression. Large eyelid lesions may cause irregular astigmatism and obstruct vision and cause amblyopia. A capillary hemangioma may get larger as well as change color with crying. Palpation of superficial lesions may cause blanching, and the lesion will have a spongy consistency. Capillary hemangiomas do not have a pulse or bruit.  Spontaneous regression often occurs after age 3 with residual scarring.[51]
• Angiofibromas, when associated with tuberous sclerosis (TB), present with dome-shaped, skin-colored to red papules with small apical telangiectatic vessels that are densest in the maxillary area, over the bridge of the nose, around the nasolabial folds, and the chin and extending onto the lower eyelid. Early on, the lesions are erythematous and flat and will grow to elevated red to red-brown lesions that may coalesce into plaques.
• Nevus flammeus (port-wine stain) presents at birth as a flat, pink, or red homogenous skin lesion with geographic borders. It is painless, does not ulcerate or bleed, and is not warm to touch. The lesions can be single or multiple, unilateral or bilateral, and often follows the trigeminal nerve distribution. The lesion grows larger and darker, may thicken, and become more nodular with age.[52]

Neurogenic

• Plexiform neurofibroma of the eyelid presents with ptosis or a classic "S-shape" of the eyelid margin. The eyelid will have rubbery linear lesions underneath the surface, and upon palpation, it can feel like there is a "bag of worms" within the eyelid. Neurofibromas associated with NF1 are usually present by age 10. Patients may develop ptosis obstructing the visual axis, proptosis, exposure keratopathy, strabismus, amblyopia, and glaucoma, especially when the plexiform neurofibroma extends into the orbit. About 50% of patients with plexiform neurofibroma will develop glaucoma in the ipsilateral eye. Between 15 and 20% of children with NF1 develop an optic nerve glioma. About 5% of plexiform neurofibromas develop into malignant peripheral nerve sheath tumors. Optic nerve compression may affect vision as well.[53][66]
• Solitary neurofibroma of the eyelid is rare and may present nonspecifically suspicious for a chalazion or with ptosis and fullness of the eyelid without pain. More common in young adults compared to the plexiform neurofibroma.[54]
• An eyelid schwannoma presents with painless, gradual growth over months to years of a deep mass that may cause ptosis.[55]

Lipomatous

• Lipomas present as soft slow-growing mass over months to years located in the zone of the eyelid that adjoins the orbital rim.[56]

Histopathology

Skin

Epidermis

• Seborrheic keratosis (SK) shows proliferation of basaloid cells with keratin-filled cystic inclusions and variable hyperkeratosis. The papillomatous variant of SK has more hyperkeratosis. The adenoid variant has less hyperkeratosis and contains more elongated epithelial strands. The lesion is histologically located above the skin surface. Irritation of the lesion can cause chronic inflammation of the dermis.[16]
• Dermatosis papulosa nigra (DPN) displays an irregular thickened layer of squamous epidermal cells (acanthosis) and the elevation of dermal papillae above the skin (papillomatosis), and hyperkeratosis of the epidermis.[57]
• Inverted follicular keratosis is considered an inflamed variant of SK by some experts. It is a subdermal lesion and displays prominent squamous eddies as well as papillomatosis and acanthosis.[12]
• Verruca vulgaris lesions are typified by a large amount of papillomatosis, acanthosis with hyperkeratosis that demonstrates apical parakeratosis. Infected cells within the lesion demonstrate contraction of the nucleus and cytoplasmic clearing (koilocytosis). A mixed inflammatory infiltrate is often present in the dermis.[58]
• Molluscum contagiosum has pear-shaped lobules of invasive acanthosis within the epidermis. There is a central cavity filled with sloughed-off epithelial cells that contain characteristic virus-containing inclusion bodies within the cytoplasm (molluscum bodies).[12]
• Squamous papilloma (acrochordon or skin tag) consists of a papillomatous structure with a fibrovascular center. It contains squamous epithelium with variable degrees of acanthosis, hyperkeratosis, and sometimes parakeratosis. Inflammation may be present.[18] 
• Epidermal inclusion cyst. Cystic structure in the dermis lined with stratified keratinized squamous epithelium with the cyst lumen filled with desquamated keratin.[12]
• Cutaneous dermoid cyst. The same as epidermal inclusion cyst except for the presence of dermal adnexal structures in the cyst wall and adnexal structures and secretions in the cyst lumen.
• Keratoacanthoma is distinguished by thickened epidermis in the shape of a cup surrounding a central plug of keratin. The epidermis will contain squamous epithelium often infiltrated with neutrophils.[12]
• A cutaneous horn is associated with several benign and malignant lesions and is a descriptive term for any lesion that has massive hyperkeratosis. The histopathologic analysis focuses on the tissue at the base of the cutaneous horn.[22]

Melanocytic

• Ephelis (freckles) display hyperpigmentation of the basal cells of the epidermis. There is no elongation of the rete ridges.
• Lentigo simplex lesions display an increase in the number of nevus cells (melanocytes) as well elongation of the rete ridges and the presence of melanophages in the upper dermis.
• Solar lentigo lesions also display an increase in the number of nevus cells as well elongation of the rete ridges. In addition, the rete ridges assume a club shape and are more tortuous.[12]
• Nevi[61][62][63]
  • Congenital nevi contain nevus cells in the deep dermis as well as around blood vessels and hair follicles[67]
    • Split nevus (also known as a "kissing nevus") has the histopathology of a compound nevus.[26]
    • Oculodermal melanocytosis (ODM, nevus of Ota) displays dendritic and plump polyhedral nevus cells in the deeper dermis layer.[27]
    • A giant hairy pigmented nevus contains Nevis cells in the deeper two-thirds of the dermis, including around the adnexal structures. Collagen is present as well.[30]
    • Mongolian spot nevus displays a similar distribution and type of nevus cell as ODM.[64]
    • Blue nevus is different in that dendritic nevus cells are deeper in the dermis.[31]
  • Acquired[12]
    • A Spitz nevus has the histopathology of a compound nevus with mitotic figures. Spitz nevi contain more epithelioid nevus cells.[32]
    • A Reed nevus is like a Spitz nevus with more spindle-shaped nevus cells.
    • Melanocytic nevus. A nevus contains nevus cells in the dermis and/or the dermo-epithelial junction. Nevus cells are a variant of melanocytes; they are larger, without dendrites, and have more cytoplasm containing larger granules.
      • Junctional: nevus cells are located in the dermo-epithelial junction of the skin.
      • Intradermal: nevus cells are located in the dermis.
      • Compound: nevus cells are located in both the dermis and the dermo-epithelial junction.
      • Dysplastic:  four features, intraepidermal lentiginous hyperplasia, cytological atypia of nevus cells, lamellar and concentric fibroplasia, and architectural atypia, are present in dysplastic nevi. Atypical nevus cells may form "irregular nests" within the epidermis above the basement membrane in pockets called "shoulders" that push into the dermis. These nests can be joined with bridges to "nests" in adjacent "shoulders." Any disruption of the epidermal basement membrane by atypical nevus cells is a sign of malignant melanoma.

Adnexal Lesions

• External and internal hordeola present as an abscess containing polymorphonuclear leukocytes and necrotic tissue in the Zeis and meibomian glands, respectively.[12][33]

Hair Follicles

• Trichoepithelioma reveals differentiation of the germinative cell portion of the follicle. It contains abortive hair papillae, branching nests of basaloid cells, and horn cysts. They are considered hamartomatous lesions. These lesions may have histopathological overlap with BCC.[34]
• Trichofolliculoma reveals mesenchymal differentiation of the hair follicle. It presents as a central dilated cystic hair follicle lined with stratified squamous and epithelial strands and buds showing different stages of pilar formation protruding from the wall of the lesion. It usually contains several hair shafts.[35]
• Trichilemmoma reveals differentiation of the infundibulum part of the follicle. It presents with lobules of squamous epithelial cells along with palisading cells in the periphery. The lesion often contains hair follicles.[36]
• Pilomatrixoma reveals matrical differentiation of the follicle.[37]  

Sweat Glands

• Apocrine hidrocystoma (cyst of Moll):  Presents with one or more cystic spaces surrounded by an inner layer of columnar epithelial cells and an outer layer of myoepithelial cells. Fluid in the cyst is clear or milky.[38]
• Eccrine hidrocystoma: Presents with one cystic space surrounded by two layers of cuboidal epithelial cells (no myoepithelial cells are present).
• Trichilemmal (pilar) cyst: Presents with a cystic space lined with epithelium with basophilic palisading nuclei that contain keratin and may contain calcifications.[39]
• Syringoma is composed of small ductal elements lined with two layers of epithelial cells (no myoepithelial cells) inside dense fibrous tissue.[40]
• Pleomorphic adenoma contains epithelial cells arranged in nests and bands that may contain apocrine, eccrine, or mixed glandular components. In the eyelids, the epithelial cells rest in a myxoid matrix.[41]
• Eccrine spiradenoma contains one or more nodules filled with central cells with vesicular, large, and pale nuclei surrounded by small basaloid cells with hyperchromatic nuclei.[42]

Accessory lacrimal glands are located at the conjunctival fornix (glands of Krausse), the distal edge of the tarsal plate (glands of Wolffring), and within the caruncle (glands of Popov)

• Pleomorphic adenoma presents with a lobular lesion containing a myxoid stroma with cords of epithelial cells and small areas of cartilaginous differentiation.[43]
• In one study of 15 excised oncocytomas, three different histological types were identified with the lesion containing (1)  tubules with dilated lumens filled with mucin and lined by tall columnar epithelium, (2) cysts with epithelial projections of the cyst wall, (3) a trabecular pattern of cuboidal or polygonal cells combined with tubules and cysts.[43]

Sebaceous Glands

• Chalazion originates in the meibomian gland or gland of Zeis and presents as a mass of granulation tissue and inflammatory cells, including lymphocytes and lipid-laden macrophages surrounding clear spaces.[12]
• A sebaceous cyst (steatocystoma) and cyst of Zeis has a squamous stratified jagged lining with sebaceous glands lining and connecting to the cyst lumen.
• Sebaceous gland hyperplasia presents as an umbilicated lesion containing sebaceous glands that are larger than normal.
• Sebaceous gland adenoma presents similarly to sebaceous gland hyperplasia except that dense layers of blue basaloid cells surround the glands. Cystic spaces and more immature sebocytes are also present compared to sebaceous hyperplasia.

Stromal Lesions

Xanthelasma: lipid-laden histiocytes are visualized in the superficial dermis around blood vessels and adnexa.[65]

Vascular Lesions  

• Pyogenic granuloma presents as a collection of capillaries organized into lobules, each with a central feeder vessel. These thin-walled capillaries are embedded in a fibrous stroma that contains fibroblasts and inflammatory cells.[50]
• Capillary hemangiomas are classified as hamartomas or abnormal proliferation of normal tissue in a normal location, namely endothelial cells. Histologically, the appearance of these lesions depends on the stage of the evolution. Early lesions may be very cellular, with solid nests of plump endothelial cells and little vascular lumen. Established lesions comprise well-developed, flattened, endothelium-lined capillary channels of varying sizes in a lobular configuration. Involuting lesions show increased fibrosis and hyalinization of capillary walls with luminal occlusion.[51]
• Angiofibromas present proliferation of stellate and spindled cells around blood vessels within the dermis with the overlying epidermis pushed up and atrophic.[12]
• Nevus flammeus (port-wine stain) presents with a high density of telangiectatic capillaries containing a single cell layer of endothelial cells located in the dermis and subcutaneously.

Neurogenic

• Each plexiform neurofibromatosis unit is surrounded by a thickened perineurium and contains axons, Schwann cells, and endoneurial fibroblasts.[12]
• The solitary neurofibroma presents without a clear perineurium but is enclosed within a pseudo-capsule instead. The lesion contains collagen in the stroma and bundles of peripheral nerve sheath cells.
• Schwannoma presents as an encapsulated lesion containing compact spindle cells and/or larger, round, clear cells with Antoni A and Antoni B patterns, respectively. Cells should have strong S-100 immunoreactivity.[12] 

Lipomatous

• Lipomas contain mature adipocytes with a small eccentric nucleus alongside thin fibrous septa containing blood vessels. Lipoblasts should not be present.[56]

History and Physical

Eyelid lesions are evaluated in the clinic with the naked eye or with a biomicroscope providing between 10 to 40X magnification. A dermatologist may employ dermoscopy that provides about 10X magnification.[68] Standard dermatological evaluation techniques of superficial lesions of the body should be used. This includes a description of the:

• Anatomical location relative to other structures such as the orbital rim, eyebrow, and eyelid margin
• Size: It can be measured with a measuring stick or the slit lamp beam
• Shape:  For example, papillomatous, dome-shaped, flat, and spherical
• Surface appearance and color:  For example: smooth, rough, ulcerated, necrotic, red, inflamed, dark brown
• Consistency:  A range from hard to firm to soft can be used
• Fluctuation: Pressing the lesion between the fingers can indicate fluid or fat-filled lesions
• Mobility: Observation of whether the lesion moves with muscle contraction (of the orbicularis)
• Transillumination. This is done using a penlight. Lesions, such as cysts filled with fluid or fat, will transilluminate

History should include questions regarding predisposing factors, duration and rate of growth of the lesion, symptoms of tenderness or itching, and the presence of discharge or bleeding. When an associated systemic disease, including inherited syndromes, is suspected, applicable questions of pertinent family history and exam findings by other specialists will need to be determined.

Evaluation

Besides visual observation with a biomicroscope or a dermoscope, other tests that may be done are:

• Biopsy and histopathological analysis: the biopsy may be incisional or excisional.
• CT or MRI scans: These tests may be done to determine the size and extent of the lesion.[69]
• Photography: This may be done to follow growth over time in lesions that are not removed.
• High-resolution ultrasound: a technique to analyze buried lesions that are deeper in the eyelid.[70]

Treatment / Management

Skin

Epidermis

• Seborrheic keratosis (SK) is best treated with shave excision at the junction of the dermis and epidermis.[16]
• Dermatosis papulosa nigra (DPN). These lesions are often observed as removal may cause scar formation and dyspigmentation. When treated, snip excision, light curettage or electrodesiccation, and laser treatment are all options that reduce the risk of dyspigmentation. Cryotherapy is not recommended as it increases the risk of hypopigmented scar formation.[57]
• Inverted follicular keratosis is best treated with biopsy and complete excision. It is likely to recur if the lesion is not completely removed.
• Verruca vulgaris recommended treatment is surgical excision or cryotherapy.[58]
• Molluscum contagiosum treatment options include excision, cryotherapy, or curettage. Home treatments such as salicylic acid or benzoyl peroxide are not recommended to be used close to the eye. The secondary follicular conjunctivitis resolves after these virus shedding lesions are removed from around the eye.[71]
• Squamous papilloma (acrochordon or skin tag) is removed by surgical excision or shave biopsy.[18]
• Epidermal inclusion cysts (epidermoid cysts). Excision or marsupialization. Milia, which are small epidermal inclusion cysts, are often surgically removed with a "deroofing" technique using a needle to remove the epidermis directly above the cyst.[60]
• Cutaneous dermoid cyst. Treatment is similar to epidermal inclusion cysts.[20]
• Keratoacanthoma is best excised with 4 mm margins due to the association with squamous cell carcinoma. In cosmetically sensitive areas, larger lesions should be removed using  Mohs micrographic surgery.[21]
• Cutaneous horns need to be removed using a complete excisional biopsy so that malignancy of the underlying cause can be ruled out.[22]

Melanocytic: Much research has been done to estimate the risk of malignant transformation of melanocytic skin lesions. Risk is assessed based on the patient history and pathophysiology of the lesion. The risk for scarring and a poor functional or cosmetic outcome is higher on the eyelids than elsewhere on the body. This is why it is recommended to refer to an oculoplastics specialist for evaluation and possible biopsy. If a biopsy is done, the histopathology of the lesion will determine whether additional treatment is needed.  

• Ephelis (freckles) and solar lentigo lesions are not thought to transform into melanoma. However, these lesions are a sign of increased light exposure and, as such, indicate an increased risk of light-induced skin malignancies.[23]
• Lentigo simplex is not thought to have malignant potential and can be observed or removed with chemical peels, surgical excision, skin laser, or cryotherapy.[24]
• Solar lentigo is not thought to have an increased rate of skin malignancy and can be observed or treated with skin lightening agents such as Cysteamine 5% cream as well as skin laser or cryotherapy. These treatments can leave scars.
• Nevi[61][62]
  • Large congenital nevi (over 20 cm in size) have an estimated 4 to 20% risk of malignant transformation.[72]  Smaller congenital nevi have a much lower risk. Blue nevi, in their pure histopathological form, are benign. However, blue nevus variants that appear similar have transformation potential, such as in blue nevus-like melanoma. Oculodermal melanocytosis requires semi-annual monitoring for glaucoma as well as melanoma of the skin, iris, and choroid.[30]
  • Acquired
    • In one study of 144 patients with Spitz type nevi, 6 developed melanoma over nine years (0.5% annual incidence).[32]
    • Melanocytic nevus. Treatment of junctional, intradermal, and compound nevi is not indicated as the transformation rate to melanoma is low. If removed, junctional nevi are less likely to recur as the nevus cells are more superficial than intradermal and compound nevi.
      • Non-dysplastic nevi (junctional, intradermal, and compound) have a relatively low risk of transforming melanoma. One study reported a rate of transformation of 1 in 200,000 of any non-dysplastic nevus for men and women under the age of 40 years. However, over 40, the risk of transformation goes up, and by age 80, the risk of any mole converting to melanoma is 1 in 3000 for males and 1 in 11,000 for females.[73]
      • The presence of dysplastic nevi is a strong risk for melanoma. In one study, subjects with one dysplastic nevus had a 1.6 increased odds ratio of melanoma, while patients with over four nevi had a 10.5 odds ratio. The risk of a single dysplastic nevus transforming is still quite low and estimated to be about 1 in 40,000 for females and 1 in 30,000 for males.[73]

Adnexal Lesions 

• Internal and external hordeolum is best treated with hot compresses and topical and oral antibiotics such as cephalosporins and sulfonamide/folic acid inhibitor combination drugs. The presence of visible purulent material within the lesion, also called a "point" or pustule, significant pain, and eyelid edema and erythema (indicating a concomitant preseptal cellulitis) require the use of an oral antibiotic to avoid further spread and prevent orbital cellulitis. In the case of a recalcitrant hordeolum, a referral within 2 or 3 days for incision and drainage is indicated. External hordeola are often at the base of an eyelash. In this case, epilation of the lash may allow for the draining of the lesion. The practitioner is cautioned against trying to express a hordeolum, especially when a clear point is not visible, as this is extremely painful and may cause preseptal cellulitis.[44] 

Hair Follicles

• Trichoepithelioma: different treatments have been reported that include laser treatment, skin transplantation, electrodesiccation, imiquimod, and retinoic acid application.[34]
• Trichofolliculoma is recommended to be removed using simple surgical excision.[35]
• Trichilemmoma is recommended to be removed using a shave biopsy to provide a better cosmetic outcome.[36]
• Pilomatrixoma is recommended to be surgically excised with wide surgical margins to avoid recurrence.[37]

Sweat Glands  

• For apocrine and eccrine hidrocystomas, electrocautery, trichloroacetic acid, and excision are preferred over incision-and-draining as removing the cyst wall is necessary to prevent a recurrence. For multiple lesions, CO2 laser and, in one report, botulinum toxin A injection were used.[38]
• Trichilemmal cysts are recommended to be completely excised to avoid recurrence.[39]
• Syringoma can be removed with a CO2 laser, excision, dermabrasion, trichloroacetic acid, electrocautery, electrodesiccation, and cryotherapy. Since the lesion is deep in the dermis, it often can not be treated completely, and recurrence is common.[40]  
• Pleomorphic adenoma is recommended to be completely excised with a few millimeters of margin to avoid recurrence.[41]
• Eccrine spiradenoma is recommended to be surgically excised. Multiple lesions can be removed with a CO2 laser.[42]

Accessory Lacrimal Glands

• Complete excision of pleomorphic adenoma and oncocytoma is recommended.[43]

Sebaceous Glands

• Chalazion and internal hordeolum are best treated with hot compresses, lid hygiene, topical and oral antibiotics including azithromycin and doxycycline, and antimicrobial lid wipes containing hypochlorous acid or tea tree oil, steroid injection, and surgical excision. In one study, 85 % of patients received non-surgical treatment; incision and curettage were performed in 15% of eyes and intralesional steroid injection in 0.55% of eyes.[74]
• Cyst of Zeis, sebaceous cyst, sebaceous gland hyperplasia, and sebaceous gland adenoma are all best excised and sent for histopathological analysis.[46]  

Stromal Lesions

Xanthelasma: Surgical excision, CO2 laser, topical 100% trichloroacetic acid. The recurrence rate is high. One study determined a 40% and 60% recurrence rate after primary and secondary excision, respectively.[65][75]

Vascular Lesions          

• Up to 90% of pyogenic granulomas can be treated with topical corticosteroids. Topical beta-blockers such as timolol have also been shown to be effective in causing regression of the lesion. If the lesion is small enough to be observed, it may spontaneously regress. For those lesions that do not respond to topical steroids, a referral for complete excision is recommended.[76][77]
• To determine the extent of the capillary hemangioma, imaging in the form of ultrasound, CT, or MRI imaging when deeper lesions are suspected should be done. Capillary hemangiomas can be associated with Kasabach-Merrit syndrome, Microangiopathic hemolytic anemia, PHACES syndrome, and Maffucci syndrome. A referral for evaluation for these syndromes is indicated. When a capillary hemangioma causes mechanical ptosis, treatment for amblyopia may need to be implemented. Testing for exophthalmos and strabismus should be performed as well. Since, in 80% of cases, the hemangioma will have regressed by age 8, management is often to avoid sequelae such as amblyopia, strabismus, optic nerve compression, and tissue necrosis as well as cosmetic considerations. First-line treatment is systemic beta-blockers or oral and intralesional corticosteroids. Surgical treatment can include CO2 and other laser photocoagulation treatments for more superficial lesions. Radiation and surgical excision are options as well.[51]
• Treatments for angiofibromas of the face include superficial ablation and vascular ablation with lasers, as well as shave excision and electrodesiccation. Sirolimus ointment has been used successfully in reducing the severity of facial angiofibromas. If angiofibromas are associated with tuberous sclerosis, referrals to the appropriate specialists will be necessary.[13]
• Nevus flammeus (port-wine stain) in the case of Sturge Weber syndrome (SWS), the patient needs to be evaluated for ocular sequelae associated with SWS that includes glaucoma and choroidal hemangiomas. Eye findings to look for are Haab striae, corneal edema, buphthalmos, tomato-catsup fundus, skin-, conjunctival-, episcleral- and choroidal-hemangiomas, heterochromia irides, retinal vascular tortuosity, and arteriovenous communications. In young patients, this may require an evaluation under anesthesia. Medical and surgical glaucoma treatment may need to be implemented, and pulsed dye laser photocoagulation for cosmesis, as this has shown a marked increase in quality of life for affected individuals.[52]

Neurogenic

• Patients with plexiform neurofibroma of the eyelid will need eye exams at least every six months until the age of eight to evaluate for rapid worsening of the eyelid ptosis, glaucoma, strabismus, proptosis, amblyopia, optic nerve edema or atrophy, visual field loss, afferent pupillary defect, and exposure keratopathy. Amblyopia is the most significant concern for vision loss in these patients. The frequency of evaluations after the age of 9 can be less than every six months, depending on the severity of the disease. Communication with other specialists in the medical team is essential. The timing of surgical intervention depends on the level of ophthalmic complications.[53]
• Solitary neurofibroma management includes testing for neurofibromatosis and observation or surgical excision if medically indicated.[54]
• Schwannoma surgical management consists of complete excision with a clear margin to allow histopathological analysis and prevent a recurrence. Recurrence of incompletely excised lesions has been more aggressive. Since vestibular schwannoma is associated with neurofibromatosis type 2, a referral for testing for neurofibromatosis may also be made.[55]

Lipomatous

• Lipomas can be observed or surgically removed when needed. Care should be taken to remove the whole capsule to reduce the chance of recurrence.[56]

Differential Diagnosis

Skin

Epidermis

• Seborrheic keratosis can appear similar to melanoma, squamous and basal cell carcinoma. In one study of 9204 lesions clinically diagnosed as SK, 0.7% were later histologically identified as melanoma.[16]
• Dermatosis papulosa nigra (DPN) appears like pigmented forms of seborrheic keratoses, acrochordons, verrucae vulgaris, melanocytic elevated nevi, several vascular and adnexal lesions such as trichoepitheliomas, tricholemmomas, and syringomas.[57]
• Inverted follicular keratosis can be mistaken for squamous cell carcinoma, keratoacanthoma, seborrheic keratosis, verruca vulgaris, and trichilemmoma. Pathophysiological and histopathological criteria such as whether the lesion is exophytic vs. downward growing, the presence of squamous eddies, basal palisading, and atypical and dysplastic cells can help distinguish among these lesions.[17]  
• Verruca vulgaris can appear similar to actinic keratosis, cutaneous horn, SCC, molluscum contagiosum, seborrheic keratosis, and dermatosis papulosa nigra.[58][78]
• The differential diagnosis of molluscum contagiosum in children includes syringoma, closed comedones, and verruca vulgaris. In immunocompromised people, molluscum lesions may be larger and more atypical, and the differential diagnosis includes BCC, keratoacanthoma, cryptococcosis, and histoplasmosis.[71]
• Squamous papilloma can look like nevi, fibroma, actinic keratosis/SCC, BCC, sebaceous cell carcinoma, verruca vulgaris, seborrheic keratosis, chalazion/hordeolum, epidermal inclusion cyst, molluscum contagiosum, and xanthelasma.[18]
• Epidermal inclusion cysts. Milia are small epidermal inclusion cysts. Dermoid cysts of the skin, also called cutaneous dermoid cysts, appear similar but have histological differences.[60]
• Cutaneous dermoid cysts of the eyelid and orbit need to be differentiated from epidermoid cysts, lipoma, pilar cysts, neurofibroma, lymphoma, abscess, trichilemmal cyst, and pilomatrixoma.[79]
• The differential of keratoacanthoma includes SCC, BCC, amelanotic melanoma, molluscum contagiosum, prurigo nodularis, metastatic lesion to the skin, Merkel cell carcinoma, Kaposi sarcoma, lichen planus, fungal infection or mycobacterial infection, foreign body reaction, and verruca vulgaris.[21]
• Cutaneous horn can be caused by several underlying benign and malignant lesions. The most common benign lesion to cause a cutaneous horn is seborrheic keratosis. The most common malignant lesion is squamous cell carcinoma, and the pre-malignant lesion is actinic keratosis. Lesions that may be similar in appearance to a cutaneous horn are pigmented filiform verruca.[22]

Melanocytic[61][62]

• Ephelis (freckles), lentigo simplex, solar lentigo, all types of nevi, and melanoma are on the differential when assessing a pigmented lesion of the eyelid. When differentiating melanoma from other lesions, it is important to realize that only 30 percent of melanomas develop from a pre-existing nevus. One assessment method that is commonly applied is evaluation for ABCDE criteria of malignancy (Asymmetry, irregular Borders, Color variation, Diameter greater than 6 mm, Evolving). Other warning signs are if a lesion bleeds or oozes, causes itching or pain, or causes swelling beyond its borders, as well as the "Ugly Duckling" sign which considers a lesion that does not mirror surrounding ones suspicious for malignancy.[23]
• Spitz and Reed nevi resemble melanoma in that they grow rapidly, can bleed or ooze, and can be multicolored, including dark black in the case of Reed nevi. Spitz nevi tend to occur in patients under 20 years of age, while melanoma is more common in older patients. Spitz nevi tend to be smaller (<6 mm) and more symmetrical. Biopsy and histopathological analyses are usually required to make a definitive diagnosis.[80][81]

Adnexal Lesions

• External hordeolum needs to be differentiated from internal hordeolum, chalazion, preseptal cellulitis, BCC, SCC, and sebaceous gland carcinoma.[82]

Hair Follicles

• Trichoepithelioma: BCC, intradermal nevus, trichoblastoma, syringoma, trichofolliculoma, trichilemmoma, milia, epidermoid cyst, molluscum contagiosum, pilomatrixoma, cylindroma, sebaceous hyperplasia, lupus pernio.[34]
• Trichofolliculoma: BCC, epidermal inclusion cyst, trichoepithelioma[35].
• Trichilemmoma: BCC, acne vulgaris, Bowen disease, Cowden disease, cutaneous horn, schwannoma, trichofolliculoma, trichoepithelioma, folliculoma.[36]
• Pilomatrixoma: BCC, branchial cleft cyst, calcinosis cutis, chondromyxoid fibroma, melanoma, pseudolymphoma, SCC, T-cell lymphoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, metastatic carcinomas, schwannoma, dermoid cyst, eruptive vellus hair cysts, follicular infundibulum tumor, folliculitis, folliculoma, insect bites, keratoacanthoma, osteoblastoma, osteofibrous dysplasia, osteoma cutis, trichilemmoma, trichoepithelioma, trichofolliculoma, tuberculosis.[37]

Sweat Glands  

• Apocrine and eccrine hidrocystoma: BCC, blue nevus, melanoma, milia, eccrine hidrocystoma, epidermoid cyst, syringoma.[38]
• Trichilemmal (pilar) cysts: cutaneous lipomas, dermoid cyst, epidermal inclusion cyst.[39]
• Syringoma has a differential diagnosis of trichoepitheliomas, BCC, and xanthelasma.[40]
• Pleomorphic adenoma has a differential diagnosis of chalazion, dermoid cyst, and epidermal inclusion cyst.[41]
• Eccrine spiradenoma has a differential diagnosis of epidermal inclusion cyst, schwannoma, and dermatofibroma.[42] 

Accessory Lacrimal Glands

• Pleomorphic adenoma and oncocytoma, when in the glands of Wolfring or Krausse, may appear as a deep skin lesion such as chalazion, dermoid cyst, or epidermal inclusion cyst. When it presents on the caruncle nevus, BCC, SCC, and granuloma are also on the differential.[43]

Sebaceous Glands

• All sebaceous gland lesions (chalazion, internal and external hordeolum, Zeis cyst, sebaceous cyst, sebaceous gland hyperplasia, and adenoma) need to be differentiated from each other.[46]
• All sebaceous gland lesions need to be differentiated from malignant lesions of the eyelid, including BCC, SCC, and sebaceous cell carcinoma.

Stromal Lesions

Xanthelasma is usually easy to differentiate from other skin lesions; however, at times may appear similar and may need to be differentiated from xanthogranuloma, syringoma, palpebral sarcoidosis, sebaceous hyperplasia, Erdheim-Chester disease, and lipoid proteinosis.[83]

Vascular Lesions      

• Pyogenic granuloma can appear similar to hemangioendothelioma, capillary hemangioma, Kaposi sarcoma, conjunctival Spitz nevus, and neurofibroma.[84]
• Capillary hemangioma needs to be differentiated from nevus flammeus (port-wine stain)/Sturge-Weber syndrome, lymphangioma or other vascular malformations, and metastatic neuroblastoma.[51]
• Angiofibroma can be confused with acne vulgaris, intradermal melanocytic nevi, acrochordons, basal cell carcinoma, and adnexal tumors.
• Nevus flammeus (port wine stain) can appear similar to salmon patches of the face, infantile hemangiomas and cavernous hemangioma.  It also needs to be differentiated from several syndromes, including Sturge-Weber, Klippel-Treneunay, Cobb, Proteus, Rubinstein-Taybi, and Megalencephaly capillary malformation polymicrogyria syndrome.[52]

Neurogenic

• Plexiform and solitary neurofibroma, as well as schwannoma, should be differentiated from other deep neoplastic processes of the lid that include chalazion, pleomorphic adenoma, oncocytoma, sebaceous cell carcinoma, and eyelid lipoma.[85]

Lipomatous

• Lipoma should be differentiated from plexiform and solitary neurofibroma, schwannoma, chalazion, pleomorphic adenoma, oncocytoma, sebaceous cell carcinoma, orbital fat prolapse, lacrimal gland inflammation, tumor, or prolapse.[56]

Prognosis

The prognosis of benign eyelid lesions is generally good. In those cases where the lesion is responsible for another disease such as glaucoma, amblyopia, or exposure keratopathy, steps must be taken to adequately manage these diseases for good outcomes. In those cases where the benign eyelid lesion increases the suspicion of systemic diseases such as hypercholesteremia, neurofibromatosis, Sturge-Weber syndrome, or tuberous sclerosis, appropriate testing, referrals, and communication will improve outcomes as well.[86]

Complications

Complications can occur when a cancerous lesion is misdiagnosed as benign and observed without biopsy and histopathological analysis.  Another complication that can occur is if the excision of the lesion causes a functional or cosmetic deficit in the ocular structures.  Finally, poor outcomes can result from a lack of understanding by the practitioner that a benign lesion heralds the presence of a systemic disease affecting other parts of the body.[86]

Deterrence and Patient Education

Better outcomes are likely if patients are educated on:

• What constitutes a change in the benign lesion that is worrisome. An example is providing the ABCDE criteria of nevus conversion to malignancy.[87]
• What to do to reduce the risk of recurrence of the lesion: An example of this is providing instructions on the daily application of warm compresses and eyelid hygiene to prevent chalazia.
• The frequency of follow-up intervals. An example is a young patient with neurofibromatosis should be seen at least every six months.
• What other specialists need to be consulted? For example, a referral to a gastroenterologist for a patient with a Leser-Trélat sign is prudent.

Enhancing Healthcare Team Outcomes

The health care team for patients with benign eyelid lesions potentially includes the eye care provider, primary care providers, ophthalmology subspecialists, dermatologists, pathologists, neurologists, radiologists, genetics counselors, and others.

Excellent communication between these specialties, as well as a timely referral, should enhance outcomes. Up-to-date knowledge of all healthcare team members' best diagnostic and treatment modalities should enhance outcomes.[86]