Neoplasia - Eye Notes

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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

Malignancy	Description
Basal cell carcinoma	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
Squamous cell carcinoma	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
Sebaceous cell carcinoma	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
Lacrimal gland neoplasia	Proptosis, pain, diplopia Pleomorphic adenoma: mixed histology, pseudoencapsulated, can transform to carcinoma Adenoid cystic: cribiform “Swiss-cheese” appearance (aggressive) Mucoepidermoid
Rhabdomyosarcoma	Proptosis, chemosis diplopia Embryonal: eosinophilic cytoplasm Alveolar: poor prognosis Botyroid

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 (<0.8mm depth)
  - Stage 2: intermediate (0.8-4mm depth). Lymph node biopsy is indicated
  - Stage 2 (still): thick melanoma (>4mm). <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]