Embryology / Pathology

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3 Embryology / Pathology

EMBRYOLOGY
PATHOLOGY

Microbial studies
Tissue stains
Tissue fixation
Hypersensitivity reactions
Immunoglobulins
HLA system
Inflammation
Eyelid epithelial changes
Aging changes
Wounds
Ocular injuries

Embryology

Formation of eye

embryonic plate → neural plate → optic pits → optic vesicles → optic cups

Embryonic plate (Figure 3.1)

1 Ectoderm (forms eye and brain): neural ectoderm, surface ectoderm, and neural crest
2 Mesoderm
3 Endoderm
image

Figure 3-1 Neural tube formation.

Optic pit

forms at day 23 of gestation

Optic vesicle

anterolateral outpouching of primitive brain stem; evaginates on day 25 and becomes the globe

Optic vesicle induces the lens placode at day 27
Abnormalities of evagination: may result in anophthalmia, cyclopia (synophthalmia), congenital cystic eye, congenital nonattachment of the retina. Apical forebrain lesions such as synophthalmia are associated with arrhinencephaly, proboscis, ethmocephaly, trisomy 13

Optic cup (Figure 3.2)

develops embryologically as an anterolateral evagination of the forebrain

Inner layer becomes the retina
Outer layer becomes the retinal pigment epithelium
Potential space between the two becomes the subretinal space (which was the cavity of the neural tube and optic vesicle)
Cells at anterior margin of optic cup form the posterior pigment epithelium of the iris
Cells between the future iris and the future retina form the ciliary body
image

Figure 3-2 Optic cup formation.

Embryonic fissure

on undersurface of optic cups; closes on day 33 allowing pressurization of globe

Closure occurs first in midzone / equator, then extends posteriorly and anteriorly
Serves as portal for mesoderm to enter eye (i.e. hyaloid artery)
Coloboma: failure of closure of embryonic fissure; sporadic or autosomal dominant (AD); typical (located in inferonasal quadrant) or atypical (located elsewhere)

May involve retina and choroid (associated with basal encephalocele, cleft palate, and CHARGE syndrome), iris, and / or optic nerve
An eyelid coloboma is not related to closure of embryonic fissure

Microphthalmos with cyst: small, abnormal eye with cystic expansion extending posteriorly into orbit

Arises in area of and external to a choroidal coloboma; cyst usually contains dysplastic neuroectodermal tissue and may not directly connect with the eye

Optic pit: considered an atypical coloboma; associated with basal encephalocele

Hyaloid artery (Figure 3-3)

enters through embryonic fissure and forms vasa hyaloidea propria (blood supply to primary vitreous)

Intravitreal portion regresses by image months; intraneural portion becomes central retinal artery
Posterior tunica vasculosa lentis supplies the posterior lens
Retinal vascular development begins during 16th week: mesenchymal cells next to hyaloid artery form capillary network, then form arteries and veins; vessels grow centrifugally from optic disc, reach nasal ora serrata during 8th month and temporal ora 1–2 months later
3% of normal neonates have a patent hyaloid artery
Remnants of hyaloid vasculature system:

BERGMEISTER’S PAPILLAE: at optic nerve head; glial sheath of Bergmeister envelops posterior third of hyaloid artery and begins to atrophy during 7th month; epipapillary veil results if it does not fully regress
PERIPAPILLARY LOOP: vascular loop extending from optic nerve head; risk of artery obstruction or vitreous hemorrhage
MITTENDORF’S DOT: small opacity on posterior lens capsule at which hyaloid artery is attached to posterior tunica vasculosa lentis
PERSISTENT PUPILLARY MEMBRANE: thin iris strands bridging pupil; may attach to anterior lens capsule; remnants of anterior tunica vasculosa lentis

image

Figure 3-3 Hyaloid vasculature and primary vitreous during embryologic ocular development.

(From Dass AB, Trese MT: Persistent hyperplastic primary vitreous. In: Yanoff M, Duker JS (eds): Ophthalmology. London, Mosby, 1999.)

Primitive epithelial papillae

cells from inner layer of optic cup at superior end of embryonic fissure, which becomes the optic disc

Ganglion cell axons grow through
Myelination starts centrally, reaching the chiasm at image months and lamina cribrosa at birth; complete approximately 1 month after birth
Inner limiting membrane of Elschnig: covers ON, contiguous with ILM
ON may show deceptively exaggerated cupping because nerve fibers posterior to lamina cribrosa are incompletely myelinated at birth
ON hypoplasia is associated with DeMorsier’s syndrome; 13% have pituitary abnormalities

Vitreous

produced by lens, retina, and walls of hyaloid artery; contains mesenchymal cells

Primary vitreous: formed by hyaloid vascular system (vasa hyaloidea propria, which includes hyaloid canal, hyaloid vessels, and posterior portions of tunica vasculosa lentis); eventually replaced by secondary vitreous; failure to regress causes persistent hyperplastic primary vitreous (PHPV) (Figure 3-4)
Secondary vitreous: formed by retina
Area of Martegiani: extends from disc into vitreous to become Cloquet’s canal
Cloquet’s canal: junction of primary and secondary vitreous
Tertiary vitreous: zonule fibers formed from ciliary processes and lens capsule
Berger’s space: retrolental space
image

Figure 3-4 Posterior segment development.

Retina

neuroectoderm; vascularization begins at 4 months; temporal periphery is last portion to become vascularized

Development of fovea is not complete until 4 or more weeks after birth
Retinal dysplasia: abnormal proliferation of developing retina produces tubular structures with a rosette-like appearance; represents nonspecific response to disorganizing influence during development; associated with maternal LSD ingestion, Patau’s syndrome (trisomy 13), microphthalmos, congenital glaucoma, Peter’s anomaly, uveal and optic nerve colobomas, cyclopia, and synophthalmia

Choroid

requires RPE for development

Stroma is from neural crest cells
Vascular endothelium is from mesoderm
Vessel walls are from neural crest cells

Sclera

neural crest cells and mesoderm (temporal aspect)

Blue hue at birth due to thinness (see underlying uveal pigment)

Cornea

neural crest cells (2 waves)

1st wave grows between epithelium and lens, forming double layer of corneal endothelium
2nd wave grows between epithelium and endothelium; this zone is rich in hyaluronic acid and collagen fibrils
At 4 months, Descemet’s membrane develops
At 5 months, Bowman’s membrane develops

Angle

neural crest cells from peripheral cornea differentiate into chamber angle during 7th week

In 4th month, Schlemm’s canal forms
In 7th month, angle moves posteriorly
In 8th month, formation is complete; trabecular meshwork appears just before birth

Lens

at 27 days, surface ectoderm adjacent to optic vesicle enlarges to form lens placode (lens plate)

Circular indentation then occurs on lens plate, forming lens pit, which invaginates the wall of the optic vesicle until it closes to form a sphere
Basement membrane of the surface ectoderm forms the surface of the sphere (the lens vesicle) and subsequently becomes the lens capsule
Lens epithelial cells on posterior aspect of this sphere elongate and migrate first (primary lens fibers); these cells fill the core of the lens vesicle at approximately 40 days (embryonal nucleus)
At 7 weeks, anterior cells migrate toward equator and proliferate to form secondary lens fibers that encase the embryonal nucleus and form the Y sutures; Y sutures represent the meeting of embryonal and fetal nuclei (upright anteriorly, inverted posteriorly)
After 3 months, zonules of Zinn (zonular fibers) develop (Figure 3-5)
image

Figure 3-5 Lens development.

Summary

3 weeks lens placode from surface ectoderm
6 weeks lens vesicle; further development requires normal neuroretina
12 weeks tunica vasculosa lentis
28–38 weeks degeneration of tunica vasculosa lentis

Lens of a newborn is more spherical than that of an adult; therefore, anterior chamber appears shallow

Iris

rim of optic cup grows around lens and forms iris

Epithelial layers (iris pigment epithelium [IPE]; anterior pigmented and posterior nonpigmented) are from inner and outer layers of the optic cup (neuroectoderm); forms part of the blood–aqueous barrier
In 7th week, stroma forms from neural crest cells, and tunica vasculosa lentis forms
In 6th month, sphincter and dilator muscles form from neuroectoderm
In 7th month, blood vessels enter iris
In 9th month, tunica vasculosa lentis disappears
Newborn iris is usually gray-blue; development of iris color takes weeks to months, as stromal chromatophores (dendritic melanocytes from neural crest) complete their migration into uvea shortly after birth
Iris dilator muscle is immature, causing relative miosis in infancy
Retinal pigment epithelium (RPE) and posterior pigment epithelium of the iris form from the outer layer of the optic cup (have mature coloration because pigment granules develop very early in gestation)

Ciliary body (CB)

formation begins in 3rd month; fold in optic cup becomes epithelial layers of ciliary processes

In 4th month, filaments from surface cells form zonules; the major arterial circle of the iris (located in CB), the longitudinal ciliary muscle, and the ciliary processes develop
In 5th month, pars plana develops, and ciliary body stroma and ciliary muscle develop from neural crest cells adjacent to cornea
In 7th month, circular fibers of ciliary muscle differentiate
Patient’s age can be determined by analysis of CB cellularity

Nasolacrimal system

at 6 weeks, surface ectoderm is buried in mesoderm, between maxillary and lateral nasal processes

During 3rd month, the cord canalizes
Defects: may result in imperforate valve of Hasner; rarely, absent puncta or canaliculi

Eyelids

at 8 weeks, upper lids form by fusion of medial and lateral frontonasal processes; lower lids by fusion of maxillary processes and medial nasal processes

At 12 weeks, lid folds fuse
At 24 weeks, separation begins from nasal side

Embryologic tissues and their components

Neural ectoderm: sensory retina, RPE, nonpigmented ciliary body epithelium, pigmented CB epithelium (extension of RPE), IPE, iris sphincter and dilator muscle, optic nerve (neural and glial elements), sympathetic ganglion, lateral geniculate body, ocular pigment granules (RPE, CB, IPE), peripheral nerves related to eye function, erector pili muscle associated with hair follicles of the skin
Surface ectoderm: crystalline lens, corneal and conjunctival epithelium, lid epithelium, lacrimal gland, nasolacrimal system
Surface and neural ectoderm: vitreous, zonules
Neural crest cells: corneal stroma and endothelium, iris stroma, TM, chamber angle, Schlemm’s canal, sclera (except temporal portion), sheaths and tendons of extraocular muscles, ciliary muscle (nonpigmented layer of ciliary body), choroidal stroma, melanocytes, meningeal sheaths, orbital bones, connective tissue of orbit, muscular and connective tissue layers of blood vessels

S-100 STAIN: specific for neural crest–derived structures
3 WAVES OF NEURAL CREST CELL MIGRATION (during 7th week): corneal and TM endothelium, keratocytes (corneal stroma), iris stroma
ANTERIOR SEGMENT DISORDERS DUE TO NEURAL CREST ABNORMALITIES:

ABNORMAL MIGRATION: congenital glaucoma, posterior embryotoxin, Axenfeld-Rieger syndrome, Peter’s anomaly, sclerocornea
ABNORMAL PROLIFERATION: iridocorneal endothelial (ICE) syndromes
ABNORMAL TERMINAL INDUCTION: corneal endothelial dystrophies

Mesoderm: blood vessel endothelium, anterior chamber angle outflow apparatus, sclera (small area temporally), EOM, Schlemm’s canal, portion of vitreous
Mesenchyme: primitive connective tissue; originates from neural crest cells and mesoderm (Figure 3-6)
image

Figure 3-6 Time line of ocular embryogenesis.

(From Azar NJ, Davis EA: Embryology in the eye. In: Yanoff M, Duker JS (eds): Ophthalmology, 2nd edn. St. Louis, Mosby, 2004.)

Pathology

Microbial studies

Stains

Gram

bacteria, fungi

Giemsa

Acanthamoeba, fungi, and cytology; best for intranuclear inclusion bodies

Acid fast (Ziehl-Neelsen)

Mycobacterium, Nocardia

Periodic acid-Schiff (PAS)

fungi

Gomori’s methenamine silver

fungi

Calcofluor white

fungi and Acanthamoeba (binds to cell wall, visible with fluorescent microscopy)

KOH

fungi

Culture Media

Blood agar

most bacteria; very good for atypical Mycobacterium

Blood agar in 5–10% carbon dioxide

Moraxella

Chocolate (contains hemin and nicotinamide adenine dinucleotide [NAD])

Haemophilus, Neisseria

Thioglycolate

anaerobes

Sabouraud’s

fungi

Löwenstein-Jensen

Mycobacterium tuberculosis, Nocardia

Loeffler’s

Corynebacteria

Non-nutrient agar with E. coli overgrowth

Acanthamoeba

Cytology

Intracytoplasmic basophilic inclusions (Giemsa stain)

Chlamydia

Intranuclear eosinophilic inclusions (Papanicolaou stain)

herpes (Tzanck smear)

Tissue stains

Hematoxylin and eosin (H&E)

hematoxylin is specific for nucleic acids within nuclei and stains blue (basophilic); eosin is specific for most cytoplasmic organelles (such as mitochondria) and stains pink (eosinophilic)

Periodic acid-Schiff (PAS)

stains basement membrane material magenta (Descemet’s, lens capsule, Bruch’s membrane, ILM [internal limiting membrane], gutattae, drusen); also stains glycogen, fungi, conjunctival goblet cells (useful for differentiation of corneal from conjunctival epithelium)

Masson trichrome

stains collagen blue and hyaline red; used for granular dystrophy

Congo red

stains amyloid orange; used for lattice dystrophy

Crystal violet

stains amyloid red-purple; used for lattice dystrophy

Alcian blue

stains acid mucopolysaccharide blue; used for macular dystrophy

Colloidal iron

stains acid mucopolysaccharide blue; used for macular dystrophy

Oil red O

stains neutral lipids red-orange in frozen section; must be used on fresh tissue because formalin leaches out lipid

Sudan black

stains phospholipids; myelin in ON

Luxol fast blue

stains myelin blue; demyelinated plaques lose affinity for stain

Bodian

stains nerve fibers black

Mucicarmine

stains mucus pink / red; mucus-secreting adenocarcinomas (i.e. GI, breast)

Verhoeff Van Gieson

stains elastic tissue black; used for elastotic degeneration

Movat’s pentachrome

stains elastic tissue black

Wilder

stains reticulin fibers black

Alizarin red

stains calcium red-orange

von Kossa

stains calcium black; used for band keratopathy

Prussian blue

stains iron (hemosiderin, ferric ions) blue

Fontana-Masson

stains melanin black; used for amelanotic melanoma

S-100 protein

stains nevi, melanomas, schwannomas, neurofibromas, and other heterologous cell lines

Polarizing filters

for evaluating structures or deposits that have a regular molecular structure (amyloid, calcium oxalate crystals), as well as suture granulomas and vegetable foreign bodies

Tissue fixation

Orientation of globe

identify superior oblique (SO) (tendinous insertion) and inferior oblique (IO) (muscular insertion) muscles

Paraffin

embedding process for histologic examination: water is removed, organic solvents leach out lipids; PMMA is dissolved completely; to preserve lipids, fresh or frozen tissue specimens are used; paraffin must be removed before different stains are applied

Glutaraldehyde

for electron microscopy

Formalin and Bouin’s fixative

for light microscopy; 10% buffered formalin (formalin = 40% solution of formaldehyde in water); formalin stabilizes protein, lipid, and carbohydrates, and prevents postmortem enzymatic destruction of tissue

Ethyl alcohol

cytology

Fixation artifacts

Lange’s fold: fold at ora serrata in newborn eyes probably caused by unequal shrinkage of retinociliary tissues during fixation
Artifactual RD: common histologic finding, differentiated from true retinal detachment by lack of subretinal fluid, preservation of photoreceptors, and pigment attached to outer surface of rods and cones (Figure 3-7)
Clefts in corneal stroma: clear spaces within stroma; obliterated in corneal edema
image image

Figure 3-7 A, Artifact RD with no fluid, pigment adherent to photoreceptors, and normal retinal architecture. B, True RD with material in subretinal space and degeneration of outer retinal layers.

(From Yanoff M, Fine BS: Ocular pathology, 5th edn. St Louis, Mosby, 2002.)

Hypersensitivity reactions (coombs and gell classification)

Type I

anaphylactic / immediate hypersensitivity (IgE)

Example: hay fever, vernal, atopic, giant papillary conjunctivitis (GPC)

Type II

cytotoxic hypersensitivity (complement mediated)

Example: OCP, Mooren’s ulcer

Type III

immune complex deposition (Ag–Ab complex)

Example: Stevens-Johnson, marginal infiltrates, disciform keratitis, subepithelial infiltrates, Wessely ring, scleritis, retinal vasculitis, phacoanyphlaxis

Type IV

cell-mediated, delayed hypersensitivity (CD4 lymphocytes)

Example: phlyctenule, graft reaction, contact dermatitis, interstitial keratitis, granulomatous disease (TB, syphilis, leprosy), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome

Type V

stimulating antibody

Example: Graves’ disease, myasthenia gravis

Immunoglobulins

IgG

most abundant; crosses the placenta; binds complement

IgA

second most abundant; monomeric or joined by J chain; important against viral infection; found in secretions

IgM

largest; binds complement; important in primary immune response

IgD

present in newborns; not in tear film

IgE

sensitizes mast cells and tissue leukocytes; role in atopy

Hla (human leukocyte antigen) system

Major histocompatibility complex (MHC) proteins found on surfaces of all nucleated cells

In humans, MHC proteins are the HLA molecules

Gene loci are located on chromosome 6

Class I: antigen presentation to cytotoxic T cells (CD8 positive); loci A, B, C
Class II: antigen presentation to helper T cells (CD4 positive); loci DR, DP, DQ

Table 3-1 HLA associations

Uveitis  
A29 Birdshot retinochoroidopathy (90%)
B7, DR2 Presumed ocular histoplasmosis syndrome (80%)
B8, B13 Sarcoidosis
B8, B51, DR2, DR15 Intermediate uveitis
B27 (1-5% of population) Adult iridocyclitis (usually unilateral): Reiter’s syndrome (75%), ankylosing spondylitis (90%), inflammatory bowel disease (90%), psoriatic arthritis, juvenile rheumatoid arthritis (JRA) (subtype V)
B51 Behçet’s disease (70%)
DR4 Sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome
DR15 Pars planitis
DQ7 Acute retinal necrosis (50%)
External disease  
B5, DR3, DR4 HSV keratitis
B8, DR3 Sjögren’s syndrome
B12 Ocular cicatricial pemphigoid
B15 Scleritis
DR3 Thygeson’s superficial punctate keratitis (SPK)
Neuro-ophthalmology  
A1, B8, DR3 Myasthenia gravis (MG)
B7, DR2 Multiple sclerosis (MS)
DR3 Graves’ disease

Inflammation

Tissue infiltration by inflammatory cells

Types of Inflammatory Cells

Neutrophils

polymorphonuclear leukocytes (PMNs)

Primary cell in acute inflammation; phagocytosis
Multilobed nucleus
Abscess: focal collection of PMNs
Pus: PMNs and tissue necrosis

Eosinophils

Allergic and parasite-related reactions (‘worms, wheezes, weird diseases’); modulation of mast cell reactions, phagocytosis of Ag–Ab complexes
Bilobed nucleus, granular cytoplasm

Mast cells

tissue basophils

IgE bound to surface; Ag causes degranulation with release of histamine and heparin

Example: anaphylaxis, allergic conjunctivitis

Looks like plasma cell

Lymphocytes

Main cell in humoral and cell-mediated immune reactions
Types: B cells, T cells (helper, suppressor, cytotoxic, killer, null cells)
Scanty cytoplasm

Plasma cells

activated B cells

Synthesis and secretion of antibodies
Eccentric ‘cartwheel’ nucleus, basophilic cytoplasm
Plasmacytoid cell: granular eosinophilic cytoplasm
Russell body: immunoglobulin crystals

Macrophages

histiocytes, monocytes (Figure 3-8)

Primary phagocytic cell; second line of cellular defense; regulation of lymphocytes via Ag presentation and monokine production
Transformation into epithelioid and giant cells
Kidney-shaped nucleus
image

Figure 3-8 Macrophage differentiation.

(Modified from Roitt IM, Brostoff J, Male DK: Immunology, 2nd edn. London, Gower Medical, 1989.)

Epithelioid histiocyte

activated macrophage with vesicular nucleus and eosinophilic cytoplasm; cells resemble epithelium; hallmark of granulomatous inflammation; fuse to form giant cells

Giant cells

3 types

Langhans’: nuclei arranged around periphery in ring / horseshoe pattern

Example: TB, sarcoidosis

Touton: midperipheral ring of nuclei; central eosinophilic cytoplasm; nuclei are surrounded by clear zone of foamy lipid

Example: juvenile xanthogranuloma (JXG)

Foreign body: nuclei randomly distributed; surrounds or contains foreign body

Types of Inflammation

Acute

Suppurative: neutrophils
Nonsuppurative: lymphocytes

Chronic

Nongranulomatous: lymphocytes and plasma cells
Granulation tissue in reparative phase; exuberant response causes pyogenic granuloma
Granulomatous: epithelioid histiocytes; 3 patterns

DIFFUSE: epithelioid cells distributed randomly against background of lymphocytes and plasma cells

Example: sympathetic ophthalmia, fungal infection, JXG, lepromatous leprosy

DISCRETE: epithelioid cells form nodules with giant cells, surrounded by rim of lymphocytes and plasma cells

Example: sarcoidosis, miliary TB, tuberculoid leprosy

ZONAL: palisaded giant cells surround central nidus

Example: phacoantigenic endophthalmitis (phacotoxic uveitis is nongranulomatous); rheumatoid scleritis (nidus = scleral collagen); chalazion

Endophthalmitis: inflammation involving at least one ocular coat and adjacent cavity, sclera is not involved
Panophthalmitis: suppurative endophthalmitis also involving sclera and orbit

Sequelae of Inflammation

Cornea

scarring

Calcific band keratopathy: basophilic granules in Bowman’s membrane
Inflammatory pannus: subepithelial fibrovascular and inflammatory ingrowth with destruction of Bowman’s membrane

Example: trachoma

Degenerative pannus: fibrous tissue between epithelium and intact Bowman’s membrane

Example: chronic corneal edema

Anterior chamber

organization of hypopyon; retrocorneal fibrous membranes

Peripheral anterior synechiae (PS): seclusio pupillae (if 360°)
Pupillary membrane: occlusio pupillae

Lens

Anterior subcapsular cataract: fibrous plaque beneath folded anterior capsule, secreted by irritated metaplastic anterior epithelial cells
Posterior subcapsular cataract: bladder cells adjacent to capsule

Ciliary body

Cyclitic membrane: retrolental collagenous membrane attached to CB; contraction leads to detachment of pars plana, ciliary muscle remains adherent to scleral spur attachment; due to organization and scarring of vitreous, metaplastic ciliary epithelium, organized inflammatory residua

Retina

CME: retinal vascular leakage or Müller cell edema
RPE changes: hypertrophy, hyperplasia, and migration (pseudoretinitis pigmentosa); fibrous metaplasia (collagen and basement membrane material deposited on Bruch’s membrane, contain lacunae of RPE cells [pseudoadenomatous proliferation]); intraocular bone from osseous metaplasia
Reactive gliosis

Phthisis

rectus muscle traction on hypotonous globe causes squared-off appearance; thickened sclera, high incidence of retinal detachment and disorganization, calcareous degeneration of lens

Eyelid epithelial changes

Hyperkeratosis

thickening of the keratin layer; clinically appears as white, flaky lesion (leukoplakia)

Parakeratosis

thickening of the keratin layer with retention of nuclei; indicates shortened epidermal regeneration time; granular layer is thin or absent

Dyskeratosis

keratin formation within the basal cell layer or deeper

Acanthosis

thickening of the squamous cell layer due to proliferation of prickle cells

Acantholysis

loss of cohesion between epidermal cells with breakdown of intercellular junctions, creating spaces within the epidermis; occurs in pemphigus and produces intraepithelial bullae

Dysplasia

disorderly maturation of epithelium with loss of polarity, cytologic atypia, and mitotic figures found above the basilar layer

Mild: <50% epidermal thickness involved
Severe: >50% involved

Carcinoma in situ (CIN)

full-thickness replacement of epithelium by malignant cells without invasion through the basement membrane

Squamous cell carcinoma

malignant epithelial cells invade below basement membrane

Anaplasia

cytologic malignancy with pleomorphism, anisocytosis, abnormal nuclei, and mitotic figures

Papillomatosis

proliferation of dermal papillae, causing surface undulation

Pseudoepitheliomatous hyperplasia

inflammatory response with hyperplasia of epithelium, which mimics carcinoma; acanthosis with protrusion of broad tongues of benign epidermis into the dermis

Elastosis

actinic damage; seen as blue staining (normally pink) of superficial dermal collagen with H&E stain; damaged collagen stains with elastic tissue stains but is not susceptible to digestion with elastase (Figure 3-9)

image

Figure 3-9 Elastosis demonstrating basophilic degeneration of conjunctival substantia propria in a pinguecula.

(From Yanoff M, Fine BS: Ocular pathology, 5th edn. St Louis, Mosby, 2002.)

Aging changes

Cornea

Hassal-Henle warts (excrescences and thickenings of Descemet’s membrane in corneal periphery)

Ciliary epithelium

hyperplasia and proliferation

Pars plana and pars plicata

clear (teardrop) cysts

Retina

loss of retinal cells and replacement with glial tissue; chorioretinal adhesions and pigmentary lesions in periphery; peripheral microcystoid degeneration (Blessig-Iwanoff cysts): located in outer plexiform layer; bubbly appearance just behind ora serrata; lined by Müller cells; contain mucopolysacharides

Wounds

Wound Healing

Cornea

stromal healing is avascular; fibrosis; neutrophils arrive via tears in 2–6 hours; wound edges swell and glycosaminoglycans (keratan sulfate, chondroitin sulfate) disintegrate at edge of wound; activated fibroblasts migrate across wound and produce; takes 4–6 weeks to return to full corneal thickness collagen and fibronectin; anterior surface re-epithelializes; endothelium migrates and regenerates Descemet’s membrane

Sclera

does not heal itself; it is avascular and acellular; ingrowth of granulation tissue from episclera and choroid

Iris

no healing

Retina

scars are produced by glial cells rather than fibroblasts

Wound Complications

Epithelial ingrowth

sheet of multilayered nonkeratinized squamous epithelium over any intraocular surface; may form cyst (free-floating or attached to iris); implanted cells tend to be 2–4 cell layers thick and have conjunctival characteristics (more than corneal)

Fibrous downgrowth

proliferating fibroblasts originate from episcleral or corneal stroma; contraction can occur; can occur with a puncture wound if there is a break in Descemet’s membrane

Hemorrhage

Corneal blood staining: hemoglobin (Hgb) breakdown products are forced through endothelial cells by increased intraocular pressure (IOP); Hgb molecules are removed by phagocytic and biochemical processes
Hemosiderosis bulbi: hemosiderin contains iron; can damage essential intracellular enzyme systems
Ochre membrane: hemorrhage that accumulates on posterior surface of detached vitreous
Synchysis scintillans: accumulation of cholesterol within vitreous following breakdown of red blood cell (RBC) membranes; angular, birefringent, flat crystalline particles with golden hue located in dependent portions of globe; cholesterol dissolves during preparation of tissues in paraffin; cholesterol clefts are negative image of cholesterol crystals, surrounded by serous fluid

Box 3-1 Differential diagnostics of intraocular calcification

Retinoblastoma
Choroidal osteoma
Choroidal hemangioma
Phthisis
Osseous choristoma

Box 3-2 Differential diagnostics of intraocular cartilage

PHPV (retrolental plaque)
Medulloepithelioma
Teratoma
Trisomy 13 (Figure 3-10)
Complex choristoma of conjunctiva
image

Figure 3-10 Trisomy 13 demonstrating intraocular cartilage and retinal dysplasia.

(Reported in Hoepner J, Yanoff M: Ocular anomalies in Trisomy 13–15: an analysis of 13 eyes with two new findings. Am J Ophthalmol 74:729-37, 1972.)

Box 3-3 Collagen

Type 1: normal corneal stroma; Bowman’s membrane (highly disorganized type 1, basal lamina has type 4)
Type 2: vitreous
Type 3: stromal wound healing
Type 4: basement membranes

Ocular injuries

Blunt Trauma

Scleral rupture (weak spots)

1 Limbus (on opposite side from trauma)
2 Posterior to rectus muscle insertions
3 Equator
4 Lamina cribrosa (ON)

Uveal tract is connected to sclera in 3 places

1 Scleral spur
2 Internal ostia of vortex veins
3 Peripapillary tissue

Cyclodialysis

disinsertion of longitudinal fibers of ciliary muscle from scleral spur

Angle recession

rupture of face of ciliary body; plane of relative weakness at ciliary body face extending posteriorly between longitudinal fibers and more central oblique and circular fibers; oblique and circular muscles atrophy, changing cross-sectional shape of ciliary body from triangular to fusiform

Iridodialysis

disinsertion of iris root from ciliary body

Vossius ring

compression and rupture of IPE cells against anterior surface of lens deposit ring of melanin concentric to pupil

Lens capsule rupture

capsule is thinnest at posterior pole; cataract can form immediately; epithelium may be stimulated by trauma to form anterior lenticular fibrous plaque

Descemet’s rupture

causes acute edema (hydrops); due to minor trauma (keratoconus) or major trauma (forceps injury)

Choroidal rupture

often concentric to optic disc; risk of CNV

Sclopoteria:

choroidal rupture with overlying necrosis of retina

Retinal dialysis

retina anchored anteriorly to nonpigmented epithelium of pars plana and reinforced by vitreous base, which straddles the ora serrata; circumferential tear of retina at point of attachment of ora or immediately posterior to vitreous base attachment

Commotio retinae

temporary loss of retinal transparency; due to disruption of photoreceptor elements, not true retinal edema

Penetrating Trauma

Penetration

partial-thickness wound (into)

Perforation

full-thickness wound (through) (globe penetration is due to perforation of the cornea or sclera; globe perforation is a double penetrating injury)

Sequelae of Trauma

Phthisis bulbi

Atrophia bulbi without shrinkage: initially, size and shape of eye are maintained; with loss of nutrition: cataract develops, retina atrophies and separates from RPE by serous fluid accumulation, synechiae cause increased IOP
Atrophia bulbi with shrinkage: eye becomes soft owing to ciliary body dysfunction; internal structures are atrophic but histologically recognizable; globe becomes smaller with squared-off shape (because of tension of rectus muscles); anterior chamber (AC) collapses; corneal endothelial cell damage leads to corneal edema and opacification
Atrophia bulbi with disorganization (phthisis bulbi): globe shrinks to average diameter of 16–19 mm; most ocular contents are disorganized; calcification of Bowman’s layer, lens, retina, and drusen; bone formation in uveal tract

Intraocular Foreign Body

Copper

≥85%: noninfectious suppurative endophthalmitis
<85% (chalcosis): copper deposits in basement membranes (Kayser-Fleisher ring, sunflower cataract, retinal degeneration)

Steel (contains iron)

siderosis bulbi; follow with electroretinogram (ERG) (early increased a wave, normal b wave; later decreased b wave leading to extinguished)

Organic (vegetable matter)

severe granulomatous foreign body response

Chemical Injury

Acid

precipitates proteins; zone of coagulative necrosis acts as barrier to deeper penetration

Alkali

denatures proteins and lyses cell membranes; no effective barrier is created – therefore deeper penetration; vascular occlusion, ischemia, corneal damage during healing phase owing to collagenase released by regenerating tissue; limbal bleaching in severe cases (if limbal stem cells are depleted the corneal surface is repopulated with conjunctival cells)

Radiation

Nonionizing

depends on wavelength

Microwave: cataract
Infrared: true exfoliation of lens capsule (glassblower’s cataract)
Ultraviolet: keratitis (welder’s flash)

Ionizing

tissue damage is direct (actively reproducing cells) or indirect (blood vessels); epithelial atrophy and ulceration, dermatitis of eyelids, dysfunction of adnexa, destructive ocular surface disease with keratinization, cataract; retinal necrosis, ischemia, neovascularization, optic atrophy (retina is relatively radioresistant, but retinal blood vessels are vulnerable)

Infection (Table 3-2)

Table 3-2 Most common cause of infections

Endophthalmitis:  
Acute postoperative (<6 weeks) Coagulase-negative Staphylococcus, Staphylococcus aureus
Delayed postoperative Propionibacterium acnes, coagulase-negative Staphylococcus
From filtering bleb Streptococcus pneumoniae, Staphylococcus, Haemophilus influenzae
Post-traumatic Staphylococcus species, Bacillus cereus, Gram-negative organisms
Endogenous (IVDA) Candida
Dacryocystitis S. pneumoniae, Staphylococcus
Dacryadenitis Staphylococcus
Canaliculitis Actinomyces
Orbital cellulitis (children) S. aureus
Preseptal cellulites S. aureus
Angular blepharitis Staphylococcus, Moraxella

Tumors (Box 3-4)

Box 3-4 Tumors

Congenital:

Hamartoma: composed of tissues normally found in that area

Example: hemangioma

Choristoma: composed of tissues not normally found in that area

Example: choroidal osteoma

Most common primary malignant intraocular tumor in adults: uveal melanoma
Second most common primary malignant intraocular tumor in adults: lymphoma
Most common primary malignant intraocular tumor in children: retinoblastoma
Second most common primary malignant intraocular tumor in children: medulloepithelioma
Most common malignant lacrimal gland tumor: adenocystic carcinoma
Most common benign orbital tumor in adults: cavernous hemangioma
Most common benign orbital tumor in children: capillary hemangioma
Most common primary malignant orbital tumor in children: rhabdomyosarcoma
Most common metastasis to orbit in children: neuroblastoma

Review Questions (Answers start on page 358)

1 Which stain is the most helpful in the diagnosis of sebaceous cell carcinoma?

a Giemsa
b hematoxylin and eosin
c oil-red-O
d methenamine silver

2 Pagetoid spread is most commonly associated with

a malignant melanoma
b squamous cell carcinoma
c sebaceous cell carcinoma
d Merkel cell tumor

3 A melanoma occurring in which of the following locations has the best prognosis?

a iris
b ciliary body
c choroid, anteriorly
d choroid, posterior pole

4 Calcification in retinoblastoma is due to

a RPE metaplasia
b necrosis
c hemorrhage
d metastasis

5 The type of organism that causes Lyme disease is a

a bacillus
b spirochete
c protozoan
d tick

6 Characteristics of ghost cells include all of the following except

a khaki colored
b rigid
c Heinz bodies
d biconcave

7 A moll gland is best categorized as

a mucin
b apocrine
c sebaceous
d holocrine

8 Which of the following is not a Gram-positive rod?

a Corynebacterium
b Bacillus
c Serratia
d Listeria

9 Trantas’ dots are composed of what cell type?

a macrophage
b neutrophil
c eosinophil
d mast cell

10 Types of collagen that can be found in the cornea include all of the following except

a I
b II
c III
d IV

11 Lens nuclei are retained in all of the following conditions except

a Leigh’s syndrome
b Lowe’s syndrome
c rubella
d Alport’s syndrome

12 Vogt-Koyanagi-Harada syndrome is best described by which type of hypersensitivity reaction?

a I
b II
c III
d IV

13 Lacy vacuolization of the iris occurs in which disease?

a central retinal vein occlusion
b diabetes
c central retinal artery occlusion
d hypercholesterolemia

14 Antoni A and B cells occur in which tumor?

a neurilemmoma
b meningioma
c glioma
d neurofibroma

15 Which tumor is classically described as having a ‘Swiss cheese’ appearance?

a rhabdomyosarcoma
b adenoid cystic carcinoma
c benign mixed tumor
d meningioma

16 Which iris nodule is correctly paired with its histopathology

a JXG, inflammatory cells
b Lisch nodule, neural crest hamartoma
c Koeppe nodule, stromal hyperplasia
d Brushfield spot, histiocytes and Touton giant cells

17 Which of the following statements is true concerning immunoglobulin

a IgG crosses the placenta
b IgA binds complement
c IgM is present in newborns
d IgD is the second most abundant

18 A retinal detachment caused by fixation artifact can be differentiated from a true RD by all of the following except

a a fold at the ora serrata
b no subretinal fluid
c normal retinal architecture
d pigment adherent to photoreceptors

19 Which of the following epithelial changes in the eyelid refers to thickening of the squamous cell layer

a parakeratosis
b acanthosis
c dysplasia
d papillomatosis

20 Intraocular hemorrhage may cause all of the following sequelae except

a synchysis scintillans
b ochre membrane
c asteroid hyalosis
d hemosiderosis bulbi

21 Intraocular calcification may occur in all of the following except

a retinoblastoma
b medulloepithelioma
c choroidal hemangioma
d phthisis

22 The histopathology of which tumor is classically described as a storiform pattern of tumor cells

a rhabdomyosarcoma
b plasmacytoma
c neurilemoma
d fibrous histiocytoma

23 Which of the following findings is a histologic fixation artifact

a Lange’s fold
b Mittendorf’s dot
c Berger’s space
d Cloquet’s canal

24 The corneal stroma is composed of

a surface ectoderm
b neural crest cells
c mesoderm
d neural ectoderm

25 Neisseria is best cultured with which media

a Loeffler’s
b Sabaroud’s
c thioglycolate
d chocolate agar

26 Which of the following stains is used to detect amyloid

a colloidal iron
b Alcian blue
c crystal violet
d Masson trichrome

27 HLA-B7 is associated with

a Behçet’s disease
b presumed ocular histoplasmosis syndrome
c iridocyclitis
d sympathetic ophthalmia

28 Which of the following conjunctival lesions should be sent to the pathology lab as a fresh unfixed tissue specimen?

a lymphoma
b squamous cell carcinoma
c Kaposi’s sarcoma
d melanoma

29 Subepithelial infiltrates in the cornea from epidemic keratoconjunctivitis are thought to be

a lymphocytes and dead adenovirus
b polymorphonuclear leukocytes surrounding live adenovirus
c macrophages containing adenoviral particles
d lymphocytes and polymorphonuclear leukocytes

30 Which is the correct order of solutions for performing a Gram stain?

a iodine solution, crystal violet stain, ethanol, safranin
b crystal violet stain, safranin, ethanol, iodine solution
c iodine solution, safranin, ethanol, crystal violet stain
d crystal violet stain, iodine solution, ethanol, safranin

Suggested readings

Embryology

Mann I. The Development of the Human Eye. New York: Grune & Stratton; 1964.

Pathology

Apple DJ. Ocular Pathology: Clinical Applications and Self-Assessment, 5th edn. St Louis: Mosby; 1998.

Char PH. Tumors of the Eye and Ocular Adnexa. Hamilton, Ontario, Canada: BC Decker; 2001.

Eagle RC. Eye Pathology: An Atlas and Basic Text, 2nd edn. Philadelphia: Lippincott Williams & Wilkins; 2011.

Spencer WH. Ophthalmic Pathology: An Atlas and Textbook, 4th edn. Philadelphia: WB Saunders; 1996.

Yanoff M, Sassani JW. Ocular Pathology, 6th edn. Philadelphia: Mosby; 2008.

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