- Histologically similar tumours may behave differently within the eye, possibly due to it’s immune privileged status
- Neoplasm: proliferation of cells that is progressive, purposeless, independent of the surrounding tissue integrity and continues even after the initial stimulus has ceased
- Malignant tumour (cp benign) are irregular, non-encapsulated, fast-growing and can spread

NB: **for more on Retinoblastoma, please refer to the genetics sections**

## Carcinogenesis
- Environmental
 - Chemicals
 - Radiation: directly damages DNA leading to mutation
 - Viruses: conjunctival papillomas are caused by HPV 6 and 11 (16 and 18 are high-risk for carcinoma); EBV contributes to orbital Burkitt’s lymphoma
 - HPV produces the E6 protein which binds to and inactivates p53 leading to uncontrolled DNA replication
 - EBV produces a protein that makes the cell resistant to apoptosis

- Genetic
 - Proto-oncogenes: normal genes that stimulate cell division
 - Tumour suppressor genes: normal genes that inhibit cell division
 - Oncogenes: abnormal/cancerous genes that cause uncontrolled proliferation
 - Loss of both copies of a tumour suppressor gene like Rb is needed for cancer development

## Premalignant states
- Benign tumours: can undergo malignant change possibly after acquiring genetic mutations eg. pleomorphic lacrimal gland adenomas can transform to adenocarcinoma
- Chronic inflammation: chronic lymphocytic infiltrates in the lacrimal gland associated with Sjogren’s syndrome can develop into lymphoma
- Intraepithelial neoplasia (carcinoma in situ): actinic keratosis showed pleomorphism and dysplasia and can become squamous cell carcinoma if they breach the basement membrane

## Ocular oncology referral guidelines
### Who to refer
- Intraocular tumours
 - Any primary intraocular tumour (except for naevi)
 - Any intraocular metastatic tumour if ocular oncology input required
 - Suspected intraocular lymphoma

- Conjunctival and epibulbar tumours
- Conjunctival melanocytic tumours if:
 - Cornea, caruncle or palpebral conjunctiva involved
 - Feeder vessels
 - Nodule with diffuse pigmentation
 - Diameter greater than 3mm, especially in absence of clear cysts

- Suspicious melanocytic choroidal tumours with
 - Any of
 - Thickness >2mm
 - Collar-stud configuration
 - Documented growth

 - Or two of
 - Thickness >1.5mm
 - Orange pigment
 - Serous retinal detachment
 - Symptomatic

- Iris nodules if
 - Diameter >3mm
 - Markedly elevated
 - Secondary glaucoma/cataract
 - Angle involvement

## Benign tumours

- Papilloma: benign tumour of an epithelial surface
 - Eyelids:
 - Basal cell papilloma aka seborrhoeic keratosis
 - Squamous cell papilloma: includes molluscum contagiosum (poxvirus) and viral warts (HPV)
 - Conjunctiva: may be pedunculated or sessile (again, associated with HPV)

- Adenoma: benign tumour of glandular tissue
 - Can arise from eyelid sweat glands, sebaceous glands, meibomian glands
 - Sebaceous adenomas are commonly seen as a yellow mass at the caruncle

### Summary table: adnexal malignancy
<table>
 <tr>
 <th>Malignancy</th>
 <th>Description</th>
 </tr>
 <tr>
 <td>Basal cell carcinoma</td>
 <td>Rolled-edge, telangiectasia, central ulcer, plaque Nodular: well-defined islands of basal cells with peripheral palisades Gorlin-Goltz, Xeroderma pigmentosa, Bazex syndrome, arsenic, Albinism Imiquimod: immune response modulator stimulates apoptosis Superficial: discontinuous with buds into dermis Infiltrative/sclerosing (morphoeic): ill-defined strands of cells Micronodular: small collections of cells</td>
 </tr>
 <tr>
 <td>Squamous cell carcinoma</td>
 <td>Fast-growing, nodular ulcer, papillomatous, keratin horn Pink cytoplasm, intercellular bridges, keratin pearls. Sunlight, immunosuppression, AIDS Lymphatic dissemination (pre-auricular and submandibular nodes) Spindle cell</td>
 </tr>
 <tr>
 <td>Sebaceous cell carcinoma</td>
 <td>Blepharoconjunctivitis, mimics chalazion, BCC and SCC Nodular: lobules with foamy/vacuolated cytoplasm Muir-Torre syndrome (associated with visceral tumours) Oil red O stains lipid red Diffuse: pagetoid spread through epithelium</td>
 </tr>
 <tr>
 <td>Lacrimal gland neoplasia</td>
 <td>Proptosis, pain, diplopia Pleomorphic adenoma: mixed histology, pseudoencapsulated, can transform to carcinoma Adenoid cystic: cribiform “Swiss-cheese” appearance (aggressive) Mucoepidermoid</td>
 </tr>
 <tr>
 <td>Rhabdomyosarcoma</td>
 <td>Proptosis, chemosis diplopia Embryonal: eosinophilic cytoplasm Alveolar: poor prognosis Botyroid</td>
 </tr>
</table> 

## Melanoma

### Benign features
- Absence of mitotic activity
- No intradermal migration
- No nuclear enlargement or pleomorphism
- Melanin in superficial layers but not deep layers

### Conjunctival melanoma
- Premalignant lesions:
 - Primary acquired melanosis with atypia (75% of melanomas): conjunctival intraepithelial melanocytic neoplasia
 - Diffuse flat areas of pigmentation
 - PAM without atypia does not progress to melanoma

 - Pre-existing naevus (20%)
 - De novo: rare

- Raised pigmented of fleshy conjunctival lesion
- Metastasizes to lymph nodes, brain and other organs
- \>5mm thickness and forniceal/palpebral or caruncular lesions carry worse prognosis
- 10% mortality at 5 years, 25% mortality at 10 years

### Uveal melanoma
- Arise from the melanocytes
- Associated genes:
 - BAP1: most associated with metastasis and mortality
 - SF3B1 and EIF1AX: associated with better prognosis
 - GNAQ and GNA11: no effect on prognosis

- Relative incidence
 - Iris 8%: slow-growing, nodular tumours. Can cause secondary glaucoma
 - CB 12%
 - Choroid 80%

- Unilateral
- Majority are **amelanotic**
- Mushroom shaped classically due to subretinal spread after breaching Bruch’s membrane, but may be ovoid or nodular
- **Ocular and oculodermal melanocytosis** are associated with increased rate of **uveal** melanoma (1 in 400 in Caucasians). Due to excessive melanocytes
 - Slate-grey or bluish hyperpigmentation of the sclera (scleral involvement raises risk of **glaucoma**)
 - Bluish discoloration of periocular skin in the V1 or V2 dermatome
 - Naevus of Ota: **both** ocular and periorbital skin discolouration (typically unilateral)

- Complications
 - Exudative retinal detachment
 - Angle closure
 - Neovascular glaucoma (vasoformative factor production)
 - Spontaneous necrosis with symptoms of endophthalmitis
 - Proptosis

- Histology
 - **Callender** classification system but can only be used after enucleation
 - Spindle A: cigar-like shaped, slender nucleus, fine chromatin, indistinct nucleolus
 - Spindle B: plumper nucleus and more distinct nucleolus
 - Epithelioid: larger with more pleomorphism. 75% mortality at 15 years
 - **Mixed**: majority. 50% mortality at 15 years
 - Patterns can be assessed using periodic acid-Schiff stain

 - ISDNA (inverse standard deviation of nucleoli area): newer classification system

- Macroscopic features
 - Collar studding
 - Orbital spread
 - Subretinal fluid/secondary exudative detachment
 - Orange pigment: lipofuscin
 - Choroidal folds
 - Mushroom-shaped breaks through Bruch’s

- Prognostic parameters
 - Age
 - Male gender (poorer prognosis)
 - Size (larger basal diameter)
 - Location: CB tumours carry worse prognosis (ie. more anterior location)
 - Cell type: **epithelioid** type carry worse prognosis
 - Epithelioid: 35% 15-year survival
 - Spindle: 75% at 15 years

 - Closed loop vascular patterns (vasculogenic mimicry patterns) on PAS stain carry worse prognosis
 - Cytogenetics: loss of chromosome 3 heterozygosity (ie. **monosomy 3**); **additional copies of 8q**
 - (Chromosome **6p gain** is associated with better prognosis)
 - Extrascleral extension leads to metastasis via the vortex veins tributaries

### Eyelid melanoma
- Tumour thickness is the most important prognostic indicator
 - **Breslow** depth is the thickness from the epithelial surface to the deepest point
 - Melanoma in situ
 - Stage 1: thin/early melanoma (&lt;0.8mm depth)
 - Stage 2: intermediate (0.8-4mm depth). Lymph node biopsy is indicated
 - Stage 2 (still): thick melanoma (>4mm). &lt;50% 5 year survival
 - Stage 3: advanced (spread beyond the original tumour site)

- Lentigo maligna is the most common type of melanoma (90%)
- Nodular melanoma is the next most common (10%) \[cp. With cutaneous melanoma for which **superficial spreading type** is most common. In cutaneous melanoma, the subtype does not affect prognosis]

Histologically similar tumours may behave differently within the eye, possibly due to it’s immune privileged status Neoplasm: proliferation of cells that…

Pathology

Neoplasia

Intro

FRCOphth Part 1 Study Notes

Orbit and ocular adnexae

Orbit

Extraocular Muscles

Orbital Blood Vessels

Paranasal Sinuses

Lacrimal Glands

Tear Film

Eyelids

Blinking

Anterior segment - ocular surface

Conjunctiva

Conjunctivitis

Sclera

Cornea

Corneal Structure And Development

Corneal Physiology

AC to Lens

Angle

Ciliary Body

Aqueous Humour Dynamics

Iris

Pupil

Lens

Posterior segment

Choroid

Vitreous

Retinal Macrostructure

Neurosensory Retina

Retinal Pigment Epithelium

Neuroanatomy

Venous Sinuses

Cerebral Ventricles

Cerebral Blood Supply

Supranuclear Gaze Pathways

Head And Neck Autonomic Nervous Supply

Head And Neck Glands

Osteology

Nerves

Muscles And Pharyngeal Arches

Extraocular Nerves

Sensory Nerves

Physiology

Physics Of Blood Flow

Neuronal Control Of Blood Vessels

Oxygen-Haemoglobin Dissociation Curve

Cytochrome p450

Pituitary Gland

Thyroid Hormone Production

Insulin

Glucagon

Parathyroid Hormone

Corticosteroids

Catecholamines

Cardiac Cycle

Renal Physiology

Fluid Balance

Acid-Base Balance

Muscle Physiology

Sensory Fibres

Cutaneous Receptors

Endocytosis

Glycosaminoglycans

Condensed Ocular Biochemistry

Eye Movements

Accomodation

Vision

Visual Cycle And Phototransuction

Visual Pathway

Visual Acuity

Colour Vision

Binocular Vision

Collagen

Tissue Damage

Inflammation

Disease Entities

Wound Healing

Thrombosis / Atherosclerosis

Cell Growth

Histopathology

Nystagmus

Free Radicals And Antioxidants

Immunology

Ocular Immunology

Microbiology

Viral Infections

Bacterial Infections

Fungal Infections

Protozoa

Nematodes

Antimicrobials

Genetics

Chromosomes

Mitosis

Meiosis

Genes

Polypeptide Synthesis

Histones

MicroRNA

Hardy-Weinberg Equilibrium

Mutations

Chromosome Defects

Autosomal Inheritance

X-Linked Inheritance

Mitochondrial Inheritance

Multifactorial Inheritance