Moran CORE | EYELIDS

EYELIDS

Macroscopic Overview –Normal Eyelid:

The eyelid is comprised of several layers of tissue derived from surface ectoderm. From anterior to posterior, the layers are as follows: Skin, Muscle, Tarsus, and Conjunctiva.

Skin: keratinized stratified squamous epithelium with melanocytes, thinnest skin in the body
- Does not have a true dermis, therefore there are no rete ridges or pegs
- Dermal appendages: small fine hairs, eccrine glands, apocrine glands (of Moll), sebaceous glands (of Zeiss)
Muscle: Orbicularis oculiis a “C” shape with the nasal side open
- Has three components: pretarsal (anterior to tarsus), preseptal (superior to tarsus and anterior to septum), and orbital
Tarsus: dense fibrous connective tissue layer that houses meibomian glands and the accessory lacrimal glands of Wolfring
- In rats and rabbits, the tarsus contains cartilage; however, no cartilage in the tarsus of primates
Conjunctiva: Palpebral conjunctiva

Gross cross-section of eyelid

Trichrome stain of eyelid cross-section

H&E stain of eyelid

Tarsus and meibomian glands

Several dermatopathology terms are applicable to eyelid pathology.

Acanthosis: thickened squamous epithelium, particularly in stratum spinosum
Dyskeratosis: keratinization of normally nonkeratinized cells, particularly within stratum spinosum
Hyperkeratosis: excess superficial keratin layer(stratum corneum and granulosum)
Parakeratosis: retained nuclei present in superficial keratin layer(stratum corneum) and absent stratum granulosum

Acanthosis

Dyskeratosis

Hyperkeratosis

Parakeratosis

All three general types of glands are present in the eyelid. The lid margin contains a higher concentration of these glands.

Eccrine: secrete via exocytosis (secretory vessels coalesce with apical membrane and release product)
- Clusters of acini empty into a central lumen
- Secretory cells have eosinophilic granules in their cytoplasm
- Examples: sweat glands, lacrimal gland
- Accessory Lacrimal Gland of Krauss: empties into the fornix
- Accessory Lacrimal Gland of Wolfring: in the tarsus
Apocrine: secrete by pinching off apical portion of cell into lumen, cells have projections on microscopy
- Produce oily secretions
- Glands of Moll: secrete onto hair cell at lid margin
  - Tip: Mispronounce as Mole because moles have snouts and apocrine cells have projections.
Holocrine: secrete products when entire cell breaks apart (“kamikaze” secretion)
- Central nucleus with foamy cytoplasm
- Meibomian Glands: in the tarsus, empties at gray line of lid margin
  - Secretes oily layer of tear film
- Glands of Zeiss: secrete onto eyelash hair shaft
  - Same as sebaceous glands attached to normal hair. Only called glands of Zeiss when attached to eyelashes.

Eccrine-type lacrimal glands

Apocrine glands of Moll

Eyelashfollicle with sebaceous glands of Zeiss

Sebaceous Meibomian glands

Oil Red O Stain

Lid margin with several glands

Distichiasis

Congenital, usually autosomal dominant, condition in which the eyelashes exit through the ducts of meibomian glands.
Two rows of eyelashes
Thought to be an erroneous formation of a complete pilosebaceous unit instead of a normal meibomian gland.
Often associated with Trisomy 18 and mandibulofacial dystosis

Bacterial Infection

May be due to a bite or wound, contiguous spread from a sinus infection, or hematogenous dissemination
Common pathogens
- Bacterial: Staphylococcusaureus in hordeolum and infectious blepharitis
- Viral: molluscum contagiosum
- Fungal: blastomycosis, coccidiomycosis, aspergillosis

Hordeolum

External photo

Hordeolum

Acute Inflammatory Infiltrate

Infection of glands of Zeiss or Moll (external), or less commonly, meibomian glands (internal)
AKA Stye
Typically due to Staphylococcusaureus infection leading to the formation of a small abscess
An acute inflammatory infiltrate of PMNs along with edema, vascular congestion, and necrosisis seen histologically near hair follicles and glandular structures

Preseptal Cellulitis

Anterior to the orbital septum, which connects the edge of the tarsal plates to the orbital rim
Common in children
Often secondary to extension of a sinusitis or skin trauma
Inflammatory infiltrate (PMNs) seen amidst subcutaneous tissue, sometimes with edema, vascular congestion, or necrosis
Most frequently due to bacteria, particularly Streptococcus

Verruca vulgaris

Usually attributed to Human Papilloma Virus types 6 and 11
Warty, papillomatous lesion usually near the lid margin
Acanthosis, hyperkeratosis, parakeratosis, papillomatous fibrovascular cores
Koilocytosis: larger darker-staining nucleus with a clear cytoplasm
Infected cells occasionally show eosinophilic viral inclusion bodies
Superficial dermis shows a mixed inflammatory infiltrate
Can spontaneously regress

Molluscum contagiosum

External photo

Molluscum contagiosum

Viral inclusion cysts

Caused by a pox virus
Nodules with raised pearly border and central ulceration/umbilication
Eosinophilic viral inclusion bodies (molluscum bodies) at basal layer move toward the center and erupt at the surface
Acanthosis, especially at the edge of the ulcer
Can lead to follicular conjunctivitis

Chalazion

Bilateral chalazia

Lipogranulomatous reaction

Large, lipid-laden giant cell amongst chalazion contents

Due to backup of lipid from inspissatedmeibomian ducts
Noninfectious lipogranulomatous mixed inflammatory reaction: giant cells, foamy macrophages, lymphocytes, plasma cells, neutrophils
Can see lots of clear spaces from lipid droplets that do not stain with H&E
In old lesions, additional fibrosis and scarring present

Xanthelasma

Lipid-laden histiocytes

Yellow plaques that typically appear on the nasal side of the upper eyelids
30-40% of patients also have Hyperlipoproteinemia Type II or III
Lipid-laden histiocytes with a foamy cytoplasm and central nucleus found in the superficial dermis
- As opposed to adipose cells with a peripheralnucleus
Little to no inflammation present

Amyloid

Numerous, bilateral, symmetric, yellowish waxy nodules
Amorphous eosinophilic extracellular material
Positive staining with Congo Red
Pathognomonic apple-green birefringence under polarized light
Amyloid deposits from
- Immunoglobulin light chain fragments: plasma cell dyscrasias
- Transthyretin mutations: Familial amyloid polyneuropathy (FAP) types I & II
- Gelsolin mutations: FAP type IV (Meretoja syndrome [Lattice Corneal Dystrophy type 2])
Amyloid in eyelid skin strongly suggests asystemic process

Myxoma

Rare, benign, slow-growing tumor with smooth, gelatinous appearance that is often confused with cysts
Stellate and spindle-shaped cells with intracytoplasmic and intranuclear vacuoles
Cells surrounded by mucoid stroma with rare reticulin and collagen fibers, resembling primitive mesenchymal tissue

Epidermoid Cyst

External photo

Keratin-filled epidermoid cyst

High magnification of cyst lining

Cystic nodule that transilluminates on clinical exam
Lined with stratified squamous keratinized epithelium and often contains keratin
Often occur if a suture or previous trauma causes the epithelium to get stuck underneath
In children, often seen with compound nevi when melanocytes pull down some epithelium with them

Dermoid Cyst

Dermoid cyst

High magnification

Usually found in the orbit, but in the eyelid, typically located superior-temporally
Also lined with stratified squamous keratinized epithelium
Dermal appendages (keratin, hair follicles, sebaceous glands, eccrine glands) can be found in the wall and/or the cyst cavity itself
Lumen can contain keratin as well as hair and sebum

Eccrine Hydrocystoma

External photo

Eccrine hydrocystoma

Cystic structure that transilluminates on clinical exam
More common than apocrine hydrocystoma
Bilayered cuboidal epithelium lining
No apices protruding into lumen

Apocrine Hydrocystoma

Apocrine hydrocystoma

Clinical appearance similar to eccrine hydrocystoma
Bilayered cuboidal epithelium lining
Apical processes (“snouts”) protrude into lumen

Dacryops

Cyst arising from lacrimal gland duct
Thought to be secondary to trachoma, ocular cicatricial pemphigoid, or chemical injury
Lined by single or bilayered cuboidal epithelium or stratified squamous epithelium with goblet cells and central, fluid-filled lumen
No cellular atypia
Surrounding chronic inflammatory infiltrate may be present

Squamous Papilloma

Squamous papilloma

Low magnification

High magnification

Cross-section of fibrovascular cores

Most common benign lesion of the eyelid
Can be sessile or pedunculated
Acanthotic epithelium with crypts and cysts filled with keratin (hyperkeratosis)
Papillomatous, fibrovascular cores from the dermis extend into epidermis
Similar to verruca vulgaris, but without viral inclusions

Seborrheic Keratosis

Seborrheic keratosis

Keratin whirls

Pigmented melanocytes

Oily, stuck-on, tan or brown, well-circumscribed lesion commonly found in the elderly
Common, benign epithelial proliferation
Hyperkeratosis, acanthosis, papillomatosis, no dysplasia, keratin whorls
Leser-Trélat sign: sudden onset of multiple seborrheic keratoses, sign of malignancy (GI adenocarcinoma)

Nick’s tips: In seborrheic keratosis, there are finger-like projections of epidermis that go into the dermis, so it takes on more of a “hairy spider” appearance. However, in squamous papilloma, fibrovascular cores project up or out from the dermis into the epidermis, taking on a “gloved hand” morphology.

Trichilemmoma

Benign neoplasm of cells from the outer hair sheath
Glycogen-rich cells appear clear on microscopy
Thickened basement membrane, acanthosis
Cowden disease: autosomal dominant disease with multiple trichilemmomasand associated with breast, uterine, thyroid, and GI lesions

Keratoacanthoma

Flesh-colored nodule with central keratin crater formed due to rapid epithelial proliferation
Areas of well-differentiated squamous epithelium surround a central keratin mass
Chronic inflammatory infiltrate (lymphocytes and plasma cells) at base of lesion
Atypical cells may be present at the deep border of the lesion
Variant of well-differentiated squamous cell carcinoma with low malignant potential
Usually spontaneously involutes, leaving behind a slightly depressed scar

Actinic Keratosis

Actinic keratosis

Solar elastosis

Keratin whirls and atypia

Also has scaly, pigmented appearance similar to seborrheic keratosis
Due to solar exposure, so commonly found on sun-exposed areas
Most common precancerous cutaneous lesion
Can become a malignant squamous cell carcinoma
Epithelial findings: Solar or senile keratosis, acanthosis, hyperkeratosis, parakeratosis, atypical epithelium with nucleoli present
Dyskeratosis: indicates likelihood of becoming malignant
Dermal findings: solar elastosis, basophilic degeneration of collagen, chronic inflammatory infiltrate (lymphocytes and plasma cells)in superficial dermis

Nick’s tips: Since the basement membrane in actinic keratosis is still intact, it is essentially like carcinoma in situ of the eyelid. Make sure to include the base of the lesion in the biopsy so an invasive squamous cell carcinoma can be ruled out.

Basal Cell Carcinoma (BCC)

Ulcerated BCC

Nodular BCC

Peripheral palisading

High magnification

Nodulocystic BCC

Morpheaform BCC

Basosquamous BCC

Differentiated Adenoid BCC

Most common malignant tumor of the eyelid, 40 times more common than SCC
Most common location: lower lid
Second most common location: medial canthus (more likely to involve orbit and be deeply invasive)
Unlikely to occur on upper lid because the brow shades the upper lid
Elevated nodule with pearly, raised edges and central ulceration
Can also appear as a flat yellowish indurated plaque (morpheaform type)
Causes: sun exposure, some genetic component in familial syndromes
Characteristic islands of tumor cells with peripheral palisading of nuclei and a meaningful artifact of tumor shrinkage from surrounding tissue
Differentiated types: pluripotent cells differentiate into skin and skin appendage-like structureso
- Keratotic –hair
- Cystic –sebaceous glands
- Adenoid –apocrine & eccrine glands, cystic spaces filled with mucin
Undifferentiated types:
- Nodular: lobules of tumor cells with pseudocapsule (retraction artifact)
  - Contents can be solid or cystic
  - Nodular cystic BCC: nodular type with large areas of necrosis
  - Mostcommon type of BCC
- Ulcerative: present with surrounding chronic inflammatory infiltrate in the dermis
- Morpheaform: fingers or “Indian filing” of tumor cells with surrounding fibrous stroma
  - More aggressive form of BCC with a worse prognosis
  - More difficult to know if fully excised
- Multicentric: epidermis and superficial dermis diffusely involved
- Basosquamous: morphology between BCC and SCC and more aggressive type
Treatment: complete excision
- Mohs surgery essential for Ulcerative, Morpheaform, and Multicentric types
Prognosis
- Morbidity relates to local spread
- Metastasis extremely rare

Squamous Cell Carcinoma(SCC)

Nodule of SCC

Diffuse SCC lesion

Squamous cell carcinoma

Higher magnification

Second most common malignancy of the eyelids
Most commonly arise from actinic keratosis and sun damaged skin
More likely to involve the lower lid than the upper lidHowever, of upper eyelid malignancies, SCC is more likely than BCC.
Clinical appearance can vary from ulcers to plaques and nodular to fungating
Typical presents as a scalyorange plaque or nodule with parchment paper-like skin, madarosis (lash loss), and surrounding sun-damaged skin that may be ulcerated
Nests or strands of atypical squamous cells invading the basement membrane and dermis
- Well-differentiated: keratin whirls, intercellular bridges, dyskeratosis, acanthosis
- Spindle cell variant: appears like fibrous histiocytoma or fibrosarcoma
- Adenoid variant: pseudoglandular structures from atypical cuboidal epithelium
  - Uncommonly affects eyelid
  - Good prognosis
Treatment: wide local excision
Prognosis
- Perineural or lymphatic invasion worsens prognosis
  - Mohs surgery is indicated
- Up to 20% experience metastasis to a regional lymph node

Nick’s tips: When in doubt, a basal cell carcinoma is predominantly blue, whereas a squamous cell carcinoma will predominantly stain pink due to the presence of keratin.

Sebaceous Hyperplasia

Sebaceous hyperplasia

Uncommon benign lesion
Small yellow papule on the face and eyelid
Several sebaceous gland lobules surrounding a single central duct
Normal basal layer

Sebaceous Adenoma

Sebaceous adenoma

Rare benign eyelid lesion
Firm, yellow, circumscribed nodule
Multiple incompletely differentiated and irregularly shaped sebaceous lobules
Localized proliferation of basal basophilic sebocytes
Undifferentiated, mature, and transitional sebaceous cells present
Most commonly associated with Muir-Torre syndrome: indication of visceral malignancy (colorectal carcinoma, genitourinary, breast)

Sebaceous Carcinoma

Diffuse Sebaceous carcinoma

Focal sebaceous carcinoma

Low magnification

High magnification with mitotic figures

Oil Red O stain

A yellow-white lesion that can be diffuse or focal, sometimes with diffuse ulceration, conjunctival injection, or madarosis (lash loss)
Arise from sebaceous glands (meibomian, glands of Zeiss, in the caruncle)
Aggressive tumor that can metastasize; worse survival rates than squamous cell carcinoma
Most commonly involves the upper lid because it has twice the number of meibomian glands
Tumor cells with mitotic figures
Differentiation
- Well-differentiated: microvesicular foamy cytoplasm
- Moderately differentiated: some sebaceous differentiation
- Poorly differentiated: can be difficult to distinguish from other epithelial malignancies
Oil red O or Sudan black stain intracytoplasmic lipid in fresh tissue (frozen section) and is diagnostic
Morphology
- Lobular: basaloid features
- Comedoca: central necrotic foci
- Papillary: tumor cells in fronds with foci of sebaceous-differentiated cells
Dissemination
- Pagetoid: individual or clusters of cells invade within the epidermis or conjunctival epithelium
- Direct extension: intralymphatic, may include perineural invasion
- Vascular invasion: a distant metastasis after a regional lymph node
- Sebaceous carcinoma in situ: conjunctival epithelium completely replaced by tumor cell
Worse prognosis
- Upper lido>10mm in diameter
- Meibomian gland origin
- Symptoms > 6 months
- Infiltrative growth
- Moderate to poor differentiation
- Multicentric with pagetoid, lymphatic, or vascular invasion

Nick’s tips: A diffuse sebaceous carcinoma can mimic blepharoconjunctivitis, whereas a focal lesion can be confused with a recurrent chalazion clinically. Any loss of lashes should alert you to a more insidious process occurring.

Nevus of the Eyelid (Junctional, Compound, Intradermal)

Nevus of the eyelid margin

Compound nevus

Dermal nevus

Benign neoplasm of melanocytes
Congenital nevi: present at birth
- Typically larger
- Giant congenital melanocytic nevi: nevi > 20cm in diameter
- Risk of melanoma proportional to size
- Require close follow-up and possible excision
- Kissing nevus: nevus develops during lid fusion (Week 18 to Month 5) and involves both upper and lower lids
Nests of pigmented melanocytes classified by their location within the skin
- Junctional: nevus cells at epidermal-dermal junction
  - Clinically appear flat, retains some malignant potential
- Compound: nevus cells at junction and in the superficial dermis
  - Clinically appear raised and may increase in pigmentation
  - Retains some malignant potential, but less than junctional
  - In children, migrating melanocytes pull epithelium down with them, forming epithelial cysts
    - Presence of a nearby epithelial cysts indicates nevus present at birth (congenital) or in early childhood
- Dermal: nevus cells only within the dermis
  - Can become amelanotic
  - Giant multinucleated nevus cells and adipose tissue indicate older nevi
  - Malignant potential is lost
Intradermal nevus cell classification
- Type A: upper dermis, polygonal or epithelioid shape
- Type B: middle dermis, lymphocyte-like, smaller cell with less cytoplasm
- Type C: deep dermis, spindle-shaped, resemble Schwann cells, little to no melanin
Variants
- Balloon cell nevi: large, foamy or finely vacuolated melanocytes without atypia
- Spindle/epithelioid nevi: compound nevus in children and young adults
- Blue nevi: pigment in dermal melanocytes
- Freckle: pigment in basal layer of epidermal melanocytes
Atypical variants
- Spitz nevus
  - Develop in late childhood or adolescence
  - Larger, up to 1.0cm
  - Tan-pink color
  - Compound
  - Pleomorphic
  - Enlargement of nucleus and cytoplasm
  - No atypical mitotic figures, no intraepidermal migration, no lack of maturation
  - Increased risk of melanoma
  - Treatment: complete excision
- Dysplastic nevus
  - Size greater than 0.5cm
  - Irregular margins, irregular pigmentation
  - Atypia: nuclear enlargement, hyperchromasia(darker nucleic staining), prominent nucleoli
  - Treatment: complete excision
  - Multiple dysplastic nevi: increased risk of melanomaand possible genetic predisposition, so examine family members as well

Melanoma of the Eyelid

Melanoma of the eyelid

Low magnification

High magnification

Rarely found in the eyelids, but lower lid more common than upper
Can arise from pre-existing nevus or de novo
Signs of malignancy
- Greater than 0.5cm in size
- Irregular margins, irregular pigmentation
- Change in color, size, or shape
- Atypical cells with nuclear enlargement, hyperchromasia, prominent nucleoli
- Vertical growth leading to an elevated or indurated mass
- Crusting, bleeding, ulceration, pain, itching, tenderness
Types
- Lentigo maligna
  - Most common type on the eyelids
  - Occurs on the sun-exposed skin of the face in the elderly
  - Develops from preinvasive lesion (Hutchinson’s melanotic freckle)
  - Flat macule with variable pigmentation
  - Hyperplastic radial growth along the basal epidermis of atypical pleomorphic melanocytes
  - Follow along outer sheaths of hair shafts
- Superficial spreading
  - Most common type of cutaneous melanoma
  - Occurs on unexposed skin, typically upper back and legs, of individuals in their 50s
  - 50% arise from nevi
  - Pigmented macule with irregular outline and palpable borders
  - May have white regions signifying spontaneous regression
  - Pagetoid spreading of tumor cells in radial growth pattern close to the epidermal-dermal junction
- Nodular
  - Occurs in middle-aged patients with men twice as common as women
  - 20% arise from nevi
  - Rapidly growing blue-black or amelanotic pedunculated nodule
  - Narrow intraepidermal component
  - Prominent intradermal vertical growth, therefore more deeply invasive
- Acral-lentiginous
  - Involves extremities (palms and soles) and not eyelids
  - Similar to lentigo maligna melanoma, but atypical cells also in superficial epidermis
  - Radial growth
Lymphocytic response at base of lesion more likely to be seen in melanoma rather than a nevus.
Prognosis
- Change in lid margin, madarosis, or conjunctival involvement means worse prognosis
- In Stage I (localized) disease, prognosis correlates with depth of invasion
  - Breslow depth: measurement from upper layer of epidermis to deepest margin of the tumor in millimeters
- Can metastasize to lymph nodes
Treatment
- If no metastatic disease, wide excision with regional lymph node removal
- Stage II: can consider sentinel lymph node biopsy
- Stage III and IV: additional chemotherapy and radiation therapy

Lymphoma

External photo

Lymphoma of the Eyelid

Doughy mass of the eyelid
Does not feel hot or as if an acute infectious process is taking place
When in the eyelid, it is usually secondary to continuous spread from an orbital lymphoma
- Most orbital lymphomas are Mantle Cell lymphomas of B-cell origin
Rare tumor of the eyelid
Abundant lymphocytes (basophilic nuclei with scant cytoplasm) on histology
Lymphoma cells are not organized into follicles
Stains positive for CD20, CD5, and Cyclin D1
Monoclonality of cells can be confirmed with immunohistochemistry

Merkel Cell Carcinoma

External photo

Merkel Cell Carcinoma

Fleshy, reddish-blue lesion
Very rare tumor of the eyelid
Most commonly arise on sun-exposed areas of the head, neck, trunk, arms, and legs
Round cells look like large cell malignant lymphoma cells
High number of mitotic figures
On electron microscopy, can see dense cytoplasmic neurosecretory granules
High rate of recurrence after excision

Mucinous Adenocarcinoma

Mucinous adenocarcinoma

Mucicarmine stain

Rare tumor of the eyelid
Islands of tumor cells swimming in sea of mucin
Mucicarmine stains mucin pink or red and nuclei green
If primary lesion, can treat with wide local excision

Capillary Hemangioma

Late Capillary hemangioma

High magnification

Most common benign orbital tumor in children
May present at birth or within the first 6 months of life and grow slowly over time
Form of hamartoma, a benign growth of normal tissue in a normal location
More often present in the upper lid
Early lesions: very cellular, solid nests of endothelium, few vascular lumens
Late lesions: lobular arrangement of well-developed, flat, endothelium-lined vascular channels
Involuting lesions: increased fibrosis and hyalinization of vascular walls with lumen occlusion
Spontaneously resolve by school age

Syringoma

Benign tumor of eccrine ducts commonly seen in young women
Multiple tiny, waxy, yellow papules on the lower eyelid
Characteristic tadpole-or comma-shaped bilayered epithelium with central lumen containing colloidal material resemble paisley pattern
Dense sclerotic stroma

References:

Harper RA. Basic Ophthalmology. Amer Academy of Ophthalmology; 2010.

Yanoff M, Fine BS. Ocular Pathology, A Text and Atlas. Lippincott Williams & Wilkins; 1989.