OCULAR PATHOLOGY

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CHAPTER 18 OCULAR PATHOLOGY

EYELID

CONJUNCTIVA

INFLAMMATION

Trachoma

• Chlamydia trachomatis infection

• Immunotypes A–K

• Diagnosis by scrapings

• Follicular conjunctivitis

later papillary phase

Ophthalmia neonatorum

• Infection by Chlamydia acquired in the birth canal

• Papillary conjunctivitis

Keratoconjunctivitis sicca

• Inadequate tear film – ‘dry eyes’

• May occur in association with juvenile rheumatoid arthritis

• Conjunctiva may undergo squamous metaplasia

Granulomatous conjunctivitis

TUMORS

Epithelial inclusion cysts (Fig 18.5)

• Benign epithelial cysts

• Lined by conjunctival epithelium

• May undergo squamous metaplasia

Fig 18.5 Photomicrograph showing an epithelial inclusion cyst taken from the eyelid.

Pyogenic granuloma

• Relatively common surgical specimen from this site

• Histological features as seen elsewhere

Amyloid

• Conjunctival nodules

• Associated with systemic amyloid or local inflammation

Epithelial tumors

– placode/sessile

– pedunculated/papillary

• Premalignant/malignant tumors rare in children

Lymphoma

• Predominantly a disease of adulthood but childhood cases described

• Mostly MALT type

CORNEA

INFECTIONS

Crystalline keratopathy

• Bacterial infection in the context of topical steroids

• Clumps of bacteria

• Lacks a significant vascular or inflammatory response

Fungal keratitis

• Immunocompromise

• Purulent inflammation

• Fungal elements

Acanthameba

• Associated with contact lens use with contaminated disinfection procedures

• Atrophic epithelium

• Reduction in visible keratocytes in the stroma

• Parasitic cysts in stroma

Syphilis

• Interstitial keratitis

stroma chronic inflammation

• Ghost vessels

neovascularization of the stroma lacking circulation

INFLAMMATION

• Wegener’s granulomatosis and rheumatoid arthritis can cause corneal ulceration

DEGENERATIVE

Spheroidal degeneration

• Deposits of spheroidal structures in superficial stroma

contain keratin

• As a primary disease in excess UV exposure

• As a secondary phenomenon in inflammatory disease

Amyloid

• May occur in scarred cornea

• See also ‘Lattice dystrophy’ below

Lipid keratopathies

• May occur as secondary phenomena to neovascularization in inflammatory disease

• Crystalline stromal dystrophy (Schneider’s dystrophy)

Blood staining

• Following bleeding into the anterior chamber (hyphema)

• Blood products seep into the corneal stroma

CORNEAL DYSTROPHIES

• A range of bilateral, hereditary, progressive disorders in most cases limited to the eyes (Klintworth 2009, Poulaki & Colby 2007)

• Variable corneal opacity

• Classified according to the major anatomical layer affected

• Clinical features important in the diagnosis in many cases

• Fuchs’ dystrophy commonest in adults

does not affect children

• Important considerations in pediatric histopathological practice

lattice dystrophy

macular dystrophy

granular dystrophy

posterior polymorphous corneal dystrophy

congenital hereditary endothelial corneal dystrophy (CHED)

Epithelial and superficial dystrophies

Corneal epithelial membrane dystrophy (map dot corneal dystrophy, MDCD)

• Often asymptomatic

• Presentation typically in adults

• Recurrent corneal erosion

• Redundant basement membrane

• Intraepithelial cysts

• Usually not genetic

• Mutations in βig-H3 gene (transforming growth factor inducing gene/TGFBI) described

Meesmann’s epithelial corneal dystrophy

• Onset in early childhood

• Autosomal dominant mutations

cornea specific keratin 3 and keratin 12

• Epithelial microcysts

• Thickened basement membrane

Gelatinous drop-like corneal dystrophy

• Amyloid deposition in the epithelium, Bowman’s membrane and stroma

• Mutations in TACSTD2 (tumor-associated calcium signal transducer 2)

Reis–Buckler dystrophy

• Gaps in Bowman’s membrane with nodules of fibrous tissue

• Rod like structures by EM

• Mutations in βig-H3 gene (transforming growth factor inducing gene/TGFBI)

Thiel–Behnke dystrophy

• Similar to Reis–Buckler but with curly fibers on EM

• Mutations in βig-H3 gene (transforming growth factor inducing gene/TGFBI)

Epithelial recurrent erosion dystrophy

• Recurrent epithelial erosions

• Histology not specific

Subepithelial mucinous corneal dystrophy

• Recurrent epithelial erosions

• Subepithelial mucinous material

Stromal dystrophies

Granular dystrophy

• Clinical findings present in childhood but visual impairment later

• Stromal deposits of keratohyaline granules

stain red with Masson’s trichrome

• Mutations in βig-H3 gene (transforming growth factor inducing gene/TGFBI)

Lattice dystrophy

• Onset in childhood

• Stromal deposits of amyloid

• Mutations in βig-H3 gene (transforming growth factor inducing gene/TGFBI)

• Rare cases with mutations in GSN gene (gelsolin)

Avellino dystrophy

• Onset in second decade

• Mixture of features of granular and lattice dystrophy

• Mutations in βig-H3 gene (transforming growth factor inducing gene/TGFBI)

Schneider corneal dystrophy

• Lipid and cholesterol deposition in the anterior stroma

• Hypercholesterolemia is common

• Mutations in UBIAD1 gene

Fleck corneal dystrophy

• Rare in surgical pathology practice

• Mutations in PIP5K3 gene

• Abnormal accumulations in keratocytes

Congenital stromal corneal dystrophy

• Abnormalities in the morphology of corneal collagen

• Mutations in decorin (DCN) gene

Posterior amorphous corneal dystrophy

• Defined by clinical features

Endothelial dystrophies

Fuchs’ endothelial dystrophy

• A common dystrophy in adult practice

extremely unusual in children

Posterior polymorphous corneal dystrophy

• Major feature is the conversion of the corneal epithelium into an epithelial morphology and phenotype

may be multilayered

• May be asymptomatic

• Variable corneal edema

• Band keratopathy may develop

• Mutations in several genes have been implicated, eg VSX1, COL8A2, TCF8

X-linked endothelial corneal dystrophy (XECD)

• Focal degeneration of endothelium

• Small pits in Descemet’s membrane

CORNEAL DERMOIDS

• Congenital corneal lesion

• Epidermal structures overlying dermal connective tissue

PSEUDOPHAKIC BULLOUS KERATOPATHY

• Corneal decompensation after lens replacement (Fig 18.11)

• Loss of endothelium

• Epithelial edema

• Subepithelial bullae

Fig 18.11 Photomicrograph from a child with corneal decompensation after a lens replacement (pseudophakic bullous keratopathy). There are subepithelial bullae, stromal fibrosis and a loss of endothelium. (PAS)

CORNEAL GRAFT REJECTION AND FAILURE

• Very variable findings (Fig 18.12)

• Variable chronic inflammation

• Neovascularization

• Loss of endothelium

• Retrocorneal membrane

Fig 18.12 Photomicrograph showing a rejected corneal graft. The epithelium is starting to undergo keratinization. Bowman’s membrane is absent. There is inflammation, neovascularization and fibrosis of the stroma. There is no endothelium visible and there is a large retrocorneal fibrous plaque.

DEVELOPMENTAL ANOMALIES

ANTERIOR SEGMENTAL DEVELOPMENTAL ANOMALIES

Introduction

• Defects of the anterior segment (Sowden 2007, Nischal 2007)

ie structures anterior to the vitreous

• Traditionally a range of clinical eponyms (eg Peter’s anomaly) have been associated with these defects

Genetics

• A range of syndromes associated with PAX6, PITX2, FOXC1, FOXE3 and CYP1B1 gene mutations

• Peter’s plus (a more extensive extraocular malformation syndrome)

associated with mutations in the β-1,3-galactosyltransferase-like gene

Clinical and histopathological features

• A range of clinical syndromes associated with

corneal opacity

iridocorneal attachment

lenticulocorneal attachment

congenital glaucoma

absent or hypoplastic iris

• Multiple malformations outside the ocular system in Peter’s plus syndrome

• Correlation between traditional clinical classification, the pathological features and the genetic mutations is still evolving

Peter’s anomaly (Figs 18.13, 18.14)

• Congenital corneal opacity associated with other anterior segment defects

some feel the term is too imprecise (Nischal 2007)

• Defects in the posterior corneal structures

excavation of the central portion of the posterior stroma

absent Descemet’s membrane

absent endothelium

• Iridocorneal adhesions

Fig 18.13 Photomicrograph of a cornea from a patient with an anterior segment developmental anomaly. The central cornea is shown on the right of the image and is thinned posteriorly due to a lack of the posterior stroma, Descemet’s membrane and endothelium. To the periphery (left of the field), there is adherent iris.

Fig 18.14 Photomicrograph of a cornea from a patient with an anterior segment developmental anomaly. The central cornea is thin, lacks posterior structures and is adherent to a large degenerative lens. To the periphery there is adherent iris. (PAS)

Sclerocornea

• Corneal opacity associated with a ‘sclera’ like appearance of the cornea

• Bowman’s and Descemet’s membranes absent

• Corneal stroma lacks normal cornea architecture

resembles sclera

Congenital glaucoma

• Glaucoma arising before the age of 2 years

• Associated with enlargement of the eye (buphthalmos)

• Pathology literature limited

• CYP1B1 mutations

Persistent pupillary membrane (Fig 18.15)

• Failure to resorb developmental membrane that spans the pupil

thin fibrovascular membrane

hyperplastic membrane resembling iris stroma

Fig 18.15 Photomicrograph of the material taken from a patient with a hyperplastic persistent pupillary membrane. The tissue resembles iris stroma with an adherent thick basement membrane.

Lens malformations

• Abnormalities of lens shape

• Primary aphakia

Fig 18.16 Photomicrograph of a lens with cataractous changes from a patient with an anterior segment developmental anomaly. There is a paranuclear ring of calcification. The nucleus has a rather homogenous eosinophilic appearance.

Fig 18.17 Photomicrograph of a lens with cataractous changes from a patient with an anterior segment developmental anomaly. The image is taken from the cortex. There are vacuoles and eosinophilic globules.

MICROPHTHALMIA

• Small disorganized rudimentary eye

• May be reduced to a cyst (Fig 18.18)

• Many syndromic associations

Fig 18.18 Photomicrograph of an enucleation from a patient with microphthalmia. The globe consists of a small cystic structure lacking mature ocular tissue.

ORBITAL PATHOLOGY

• A wide range of orbital lesions may occur

• Most present non-specifically with any of the following features

reduced visual acuity

– more common in children

globe displacement / opthalmoplegia

• Combination of imaging and/or biopsy required for determination of specific diagnosis

Fig 18.19 Photomicrograph showing an infantile hemangioma in the orbit.

OPTIC NERVE PATHOLOGY

OPTIC NERVE GLIOMA

• From a pathological perspective these are typically pilocytic astrocytomas

• Associated with neurofibromatosis type 1 (Figs 18.21, 18.22)

may be associated with prominent subarachnoid infiltration

• May be extensive meningothelial proliferation

may be misleading in intraoperative diagnosis

• Atypical glial cells often seen some distance from the bulk of tumor

eg at chiasmal margin

Fig 18.21 Photomicrograph showing an optic nerve glioma from a patient with neurofibromatosis type 1. The images are longitudinal sections of the optic nerve. There is extensive subarachnoid infiltration by tumor. (Top panel – H&E, Lower panel – GFAP).

Fig 18.22 Photomicrograph showing an optic nerve glioma from a patient with neurofibromatosis type 1. The top of the image shows meningothelial proliferation and the lower part of the image shows tumor cells infiltrating the subarachnoid space.

MENINGIOMA

• Rare in childhood

INTRAOCULAR TUMORS

• In children retinoblastoma is by far the most important primary intraocular tumor (see below)

• Other tumors are rare

more common entities listed below

most occur in adults

– see standard adult ocular pathology texts

NON-RETINOBLASTOMA INTRAOCULAR ‘TUMORS’

• Iris cysts (Fig 18.23)

epithelial inclusion cyst

– lined by corneal / conjunctival epithelium

congenital stromal cyst

– lined by iris pigment epithelium

• Choroidal hemangiomas

multiple with Sturge–Weber syndrome

may be associated with retinal detachment

• Choroidal osteoma

mass of bone in the posterior choroid

• Glioneuroma of ciliary body

very rare benign congenital tumor

well differentiated CNS tissue

• Tumors of epithelium of the ciliary body

adenoma and adenocarcinoma

pigmented or non-pigmented epithelium

very rare in childhood

• Soft tissue tumors of the ciliary body

nerve sheath tumors

• Congenital hypertrophy and hyperplasia of the retinal pigment epithelium (RPE)

usually asymptomatic

rare histological specimen

may be associated with polyposis syndromes when atypical

• Retinocytoma

a benign appearing tumor resembling a well-differentiated retinoblastoma

associated with RB1 mutations

• Retinal glial tumors

astrocytic hamartomas

associated with tuberous sclerosis

rarely seen in surgical practice

Fig 18.23 Photomicrograph showing an iris containing a benign cyst.

RETINOBLASTOMA

• Highly malignant primary orbital tumor

• Most common malignant ocular tumor of childhood

overall rare: 1 in 20,000

4% of pediatric tumors

• In developed countries more than 95% of patients treated for retinoblastoma are cured

• Treated in selected specialist centers

Genetics

(Schefler & Abramson 2008, Madhavan et al 2008, Poulaki & Mukai 2009)

• Inactivation of the RB1 gene

• Inactivation of both RB1 mutations are usually thought to be necessary for tumor development

classic ‘Knudson’ two-hit hypothesis

• Sporadic retinoblastoma (60%)

no family history

usually unilateral

tend to present at a later age

– 28 months to 7 years

Clinical features

(Schefler & Abramson 2008, Kiss et al 2008)

two-thirds unilateral

one-third bilateral

known family history in 10%

• Bilateral cases usually present within first year

average 9 months

unilateral cases peak 24–30 months

• Clinical classification of tumor considered when choosing type of treatment

• Prognosis is good with early diagnosis

• Clinical classification schemes:

• Reese–Ellsworth classification system

pre-operative staging system of intraorbital disease

– based on clinical parameters

– its introduction predates common use of chemotherapy

• Long-term follow up necessary for secondary tumors

Specimen handling

(Mudhar & Bründler 2007, Ford et al 2005)

• Exenteration specimens

similar to enucleation

– always take optic nerve margin first

nearest orbital soft tissue margin

nearest cutaneous margin

Histopathological features

• Low power features (Figs 18.24–18.26)

solid sheets of small, round hyperchromatic cells

necrosis with sparing around vessels

– sometimes described as ‘pseudorosettes’ but not the same as described in ependymal tumors

calcification common

• Cytology (Figs 18.27, 18.28)

small, round hyperchromatic cells

granular chromatin

indistinct nucleoli

mitotically active

• Multifocal tumor

increased chance of germline mutation

may be difficult to distinguish from vitreal seeding

– tumor nodules on the surface of the retina favors seeding

• Treatment related changes may be seen

Fig 18.24 Photomicrograph showing an enucleation specimen containing a retinoblastoma.

Fig 18.25 Photomicrograph showing a retinoblastoma. There is extensive necrosis and viable tumor is only present around vessels.

Fig 18.26 Photomicrograph showing a retinoblastoma. There are multiple rosettes and focal calcification.

Fig 18.27 Photomicrograph showing a retinoblastoma containing Flexner–Wintersteiner rosettes.

Fig 18.28 Photomicrograph showing a retinoblastoma showing a fleurette.

Immunohistochemical staining

• Not routinely required

• Tumor cells may be positive for a range of neural markers

• Well-differentiated parts may be positive for retinal S-antigen

Differential diagnosis and diagnostic pitfalls

• Histological diagnosis is usually straightforward

• The assessment of significant choroidal involvement is poorly defined

• Distinction of multifocal disease from seeding of the vitreous may be difficult

MISCELLANEOUS OCULAR DISORDERS

EPITHELIAL DOWN-GROWTH

• Associated with corneal or limbal perforation of any cause

• Epithelium grows over posterior cornea, trabecular meshwork, iris and anterior vitreous

• Associated with glaucoma

IRIDO-CORNEAL ENDOTHELIAL SYNDROME

• Association of iris nevus, Chandler’s syndrome (corneal edema and glaucoma) and iris atrophy

• Endothelial cells contain vacuoles

• Descemet’s normal thickness

Chantada G, Doz F, Antoneli CB, et al. A proposal for an international retinoblastoma staging system. Ped Blood Cancer. 2006;47:801-805.

Ford AL, Mudhar HS, Farr H, Parsons HA. The ophthalmic pathology cut-up. Part 1: The enucleation and exenteration specimen. Curr Diagnostic Pathol. 2005;11:284-290.

Hejtmancik JF. Congenital cataracts and their molecular genetics. Semin Cell Devl Biol. 2008;19:134-149.

Madhavan J, Ganesh A, Kumaramanickavel G. Retinoblastoma: from disease to discovery. Ophthalmic Res. 2008;40:221-226.

Kiss S, Leiderman YI, Mukai S. Diagnosis, classification, and treatment of retinoblastoma. Internat Ophthalmol Clin. 2008;48:135-147.

Kitei D, DiMario FJ. Childhood orbital pseudotumor: case report and literature review. Child Neurol. 2008;23:425-430.

Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009;4:7.

Marees T, Moll AC, Imhof SM, de Boer MR, Ringens PJ, van Leeuwen FE. Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst. 2008;100:1771-1779.

Mudhar H, Bründler M-A. RCPath Dataset for the histopathological reporting of ocular retinoblastoma. Royal College of Pathologists, London, 2007. www.rcpath.org.

Nischal KK. Congenital corneal opacities – a surgical approach to nomenclature and classification. Eye. 2007;21:1326-1337.

Poulaki V, Colby K. Genetics of anterior and stromal corneal dystrophies. Semin Ophthalmol. 2007;23:9-17.

Poulaki V, Mukai S. Retinoblastoma: genetics and pathology. Internat Ophthalmol Clin. 2009;49:155-164.

Schefler AC, Abramson DH. Retinoblastoma: what is new in 2007–2008. Curr Opin Ophthalmol. 2008;19:526-534.

Sowden J. Molecular and developmental mechanisms of anterior segment dysgenesis. Eye. 2007;21:1310-1318.

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CHAPTER 18 OCULAR PATHOLOGY

EYELID

CONJUNCTIVA

INFLAMMATION

Trachoma

• Chlamydia trachomatis infection

• Immunotypes A–K

• Diagnosis by scrapings

• Follicular conjunctivitis

later papillary phase

Ophthalmia neonatorum

• Infection by Chlamydia acquired in the birth canal

• Papillary conjunctivitis

Keratoconjunctivitis sicca

• Inadequate tear film – ‘dry eyes’

• May occur in association with juvenile rheumatoid arthritis

• Conjunctiva may undergo squamous metaplasia

Granulomatous conjunctivitis

TUMORS

Epithelial inclusion cysts (Fig 18.5)

• Benign epithelial cysts

• Lined by conjunctival epithelium

• May undergo squamous metaplasia

Fig 18.5 Photomicrograph showing an epithelial inclusion cyst taken from the eyelid.

Pyogenic granuloma

• Relatively common surgical specimen from this site

• Histological features as seen elsewhere

Amyloid

• Conjunctival nodules

• Associated with systemic amyloid or local inflammation

Epithelial tumors

– placode/sessile

– pedunculated/papillary

• Premalignant/malignant tumors rare in children

Lymphoma

• Predominantly a disease of adulthood but childhood cases described

• Mostly MALT type

CORNEA

INFECTIONS

Crystalline keratopathy

• Bacterial infection in the context of topical steroids

• Clumps of bacteria

• Lacks a significant vascular or inflammatory response

Fungal keratitis

• Immunocompromise

• Purulent inflammation

• Fungal elements

Acanthameba

• Associated with contact lens use with contaminated disinfection procedures

• Atrophic epithelium

• Reduction in visible keratocytes in the stroma

• Parasitic cysts in stroma

Syphilis

• Interstitial keratitis

stroma chronic inflammation

• Ghost vessels

neovascularization of the stroma lacking circulation

INFLAMMATION

• Wegener’s granulomatosis and rheumatoid arthritis can cause corneal ulceration

DEGENERATIVE

Spheroidal degeneration

• Deposits of spheroidal structures in superficial stroma

contain keratin

• As a primary disease in excess UV exposure

• As a secondary phenomenon in inflammatory disease

Amyloid

• May occur in scarred cornea

• See also ‘Lattice dystrophy’ below

Lipid keratopathies

• May occur as secondary phenomena to neovascularization in inflammatory disease

• Crystalline stromal dystrophy (Schneider’s dystrophy)

Blood staining

• Following bleeding into the anterior chamber (hyphema)

• Blood products seep into the corneal stroma

CORNEAL DYSTROPHIES

• A range of bilateral, hereditary, progressive disorders in most cases limited to the eyes (Klintworth 2009, Poulaki & Colby 2007)

• Variable corneal opacity

• Classified according to the major anatomical layer affected

• Clinical features important in the diagnosis in many cases

• Fuchs’ dystrophy commonest in adults

does not affect children

• Important considerations in pediatric histopathological practice

lattice dystrophy

macular dystrophy

granular dystrophy

posterior polymorphous corneal dystrophy

congenital hereditary endothelial corneal dystrophy (CHED)

Epithelial and superficial dystrophies

Corneal epithelial membrane dystrophy (map dot corneal dystrophy, MDCD)

• Often asymptomatic

• Presentation typically in adults

• Recurrent corneal erosion

• Redundant basement membrane

• Intraepithelial cysts

• Usually not genetic

• Mutations in βig-H3 gene (transforming growth factor inducing gene/TGFBI) described

Meesmann’s epithelial corneal dystrophy

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