UV and the Eye

Timothy Sullivan

Professor of Ophthalmology

Glen Gole

Professor of Ophthalmology

University of Queensland

Case Summary

• Jack – 83 yo retired farmer– Past history precancerous lesions, NMSC,

cataracts– Wants a driver’s licence check

Ophthalmology

• The branch of medicine that deals with the anatomy, functions, pathology, and treatment of the eye

• Opthalmology 55%

• Optalmology 40%

• Rhinoceros 2%

• Ophthalmology3%

Subspecialties

• Anterior Segment

• Glaucoma

• Uveitis

• Neuroophthalmology

• Paediatric Ophthalmology/Strabismus

• Vitreo-Retinal

• Ocular Adnexal

• Ocular Pathology

Don’t wait for the planets to be aligned

Opportunities

• Interested Clinicians

• Basic Science Researchers

• Clinician Scientists

• Clinical Research

• Poor beaten wretches at the coal face of clinical practice

Worldwide Significance

• 45 million people are blind – 76 million by 2020

• 269 million have low vision– 145 million restored with glasses

• 90% of blind people live in low-income countries– Global economic impact $US42 Billion/year

– Restoration of sight, and blindness prevention strategies are among the most cost-effective interventions in health care

Causes of Blindness

60%

10%

15%

15%

Australian Significance

• 50 000 people are blind – 100000 by 2020

• 500 000 have low vision– 1 million by 2020– 60% refractive– 10% cataract– 10% ARMD

Ophthalmohelioses

• Ocular Adnexae

• Ocular Surface

• Lens

• Uveal Tract

• Vitreous

• Retina

• Ocular Alignment

• Systemic

Ocular Adnexae

Ocular Surface

• Keratitis– Snow blindness

• Pterygium

• Ocular Surface Squamous Neoplasia

• Reactivation Herpes

Crystalline Lens

• Early Presbyopia

• Cataract

• Pseudoexfoliation

• Dysphotopsia

Uveal Tract

• Melanoma

• Pigment Dispersion

• Uveitis

Vitreoretinal

• Liquefaction

• Solar maculopathy

• Macular Degeneration

Systemic

• Melanoma

• NMSC

• Xeroderma Pigmentosa

• Basal cell nevus syndrome

• Photosensitivity

Ophthalmic History

• Most ophthalmic conditions can be diagnosed from history alone

• Life or sight threatening systemic diseases can have ocular symptoms and signs

• Ophthalmic history taking and diagnosis require knowledge of anatomy of eye, orbit and visual pathways, pupillary responses, as well as innervation of EOM’s

History

• Specific Complaints– Pain– Foreign body sensation, ache, photophobia,

referred pain– Redness– Eye, eyelid, unilateral, bilateral , other

symptoms.

Visual Symptoms

• REMEMBER RED EYE + PAIN IS NOT CONJUNCTIVITIS

• Beware of discharge, pus,watery eyes

• Itch

• Burning stinging dryness

Visual Symptoms

• Loss of vision

• Gradual, sudden, uni -or bilateral , other symptoms “flashes, floaters” transient, permanent

• Diplopia/ Turned eyes

• Unilateral (not muscle palsy) bilateral, intermittent, directional

Visual Symptoms

• Night blindness

• Colour Vision

• Visual Phenomena

• Spots, scotomata, flashes floaters, halos

• Visual distortion

• Micropsia, macropsia, metamorphopsia

• Ptosis

• Gradual, sudden

Background

• Incidence of skin cancer in Queensland is the highest in the world– BCC 1700/year/100,000– SCC 600/year/100,000– Melanoma 56/year/100,000

• United States– 800,000 BCC/year– 200,000 SCC/year– 53,000 Melanoma/year

Layers of the skin

• Thinnest skin on body

• Epidermis– BCC basal layer– SCC more superficial– MM usually basal

• Dermis

Normal Skin Maturation (26-42Days)

• Keratinocytic Stem cells

• Basal Layer/Hair Follicles

• Divide into identical stem cells and transit amplifying cells

• Transit cells proliferate, differentiate, move upwards and are shed as squames

Skin Cancer

Disease characterised by genomic instabilityInherited mutations are termed germlineAcquired mutations are termed somatic

Rarely tumours are hereditaryMost tumours are due to

Altered DNA replicationCarcinogensDefects in DNA repair

Skin Cancer

• Two broad classes of genes contribute to cancer

• Oncogenes

• Tumour suppressor genes

Skin Cancer

• Oncogenes– Growth signaling molecules that become

activated and are perpetually turned on– Genetically dominant – Mutation of one copy of the proto-oncogene

will produce the phenotype– RAS cutaneous melanoma

Skin Cancer

• Tumour suppressor genes– Negatively regulate cell growth– Promote cell death– Both copies must be inactivated for complete loss of function

• Gatekeeper genes– Restrict cellular growth– The patched (PTC) gene– Inactivated in sporadic and hereditary BCCs

• Caretaker genes – maintain integrity of the genome– Impaired function > mutations in gatekeepers leading to

tumourigenesis (Xeroderma Pigmentosa)

Photomutagenesis

• Carcinogenic wavelengths of UV correspond to absorbtion spectrum of DNA

• UV photon absorption causes an excited state to produce dipyrimidine “photoproducts”– Predominately Cyclobutane

pyrimidine Dimer (CBD)

• Specific UV fingerprint mutations– UVB (290 – 320 nm)

• Cytosine > Thymine C > T CC > TT

– UVA (320 – 400 nm)• Thymine > Guanine T > G

Local Immunosuppression

• UV induces an environment of local immunosuppression

Langerhans Cells

Normal Epidermis

UV

Interferes with AG presentation with Langerhans Cells being the prime target

Depletes Langerhan’s Cells

Alters their dendritic morphological features

Decreases expression of Class II MHC molecules (ICAM1)

UV

Non Langerhans Inflammatory Cells

trans-Urocanic acid

cis-Urocanic acid

Abundant in stratum corneum

Converts to cis isomer with UV

Induces TNF α from keratinocytes

UV

Non Langerhans Inflammatory Cells

TNF α

Further negative effect on LC

Alters morphology

Increases depletion from the epidermis

Inhibit Contact Hypersensitivity Reaction (CHS)

UV

Non Langerhans Inflammatory Cells

TNF α IL-10

UV stimulates IL-10 production from keratinocytes Main source is from macrophages

Inhibits presentation of tumour Ag’s by APC

UV

Non Langerhans Inflammatory Cells

TNF α IL-10

Th1

UV

Non Langerhans Inflammatory Cells

TNF α IL-10

IL-12, IFN γ

IL-4, IL-10

Th1 Th2

UV alters APC function and cytokine production to sway immunosuppression from helper to suppressor pathways

UV impairs certain cell mediated immune responses and may lead to a long lived state of antigen specific tolerance and immunosuppression, predisposing to further tumours

This immunosuppression may be as important as the UV carcinogenesis in developing NMSC

BCC Aetiology

• Arise from pluripotential immature cells of the epidermis (interfollicular basal cells)

• Resemble cells of the epidermal basal layer

• Arise de novo, not from precursor lesions

BCC Aetiology

• No “promotion stage”• Involves mutations of the PATCHED gene

– Human homologue of a Drosophila gene

• UV B is the major carcinogen

Hedgehog/patched/smoothened/Gli pathway

• Mutations in PTCH causes Gorlin’s syndrome and sporadic BCC’s

• 9q22.3

Multistage Model of Carcinogenesis

• SCC conforms to this model

• Precursor lesions acquire successive genetic lesions– p53 clones– Actinic keratosis– Intraepidermal

carcinmoma– Invasive SCC

• Metastasis

Melanoma Aetiology

• Intermittent intense sun exposure– Blond/red hair, freckles and a tendency to

burn and tan poorly– > 2 episodes of painful/blistering sunburn

• Nevi– Large congenital nevi, dysplastic nevi– >50 common nevi

Melanoma Aetiology

• Arise from epidermal melanocytes– Limited capacity to proliferate– UV induces minor damage – High content of anti-apoptotic protein Bcl-2– These cells are retained possibly to

maintain then protective function of melanin– Harbour mutations and are at risk of further

mutations and malignant transformation

Genetic changes in Melanoma

• UV signature mutations rare in melanoma– P53 unlikely to play a major role in

melanoma

Genetics changes in Melanoma

• Multiple genetic alterations– Somatic activating BRAF mutation is common– Also seen in nevi, present early in progression– Activating ras mutations also seen

• Growth suppressing pathways– INK4a– PTEN (phosphatase and tensin homologue)

Melanoma Linear Tumour Progression Model

NormalNevus

VGPDysplastic RGP

Metastasis

Histological progression in melanoma

Atypical Melanocytic hyperplasia Lentigo maligna

Level 1 melanoma RGP Melanoma VGP

Sebaceous Carcinoma

Skin Lesions Management

• Is the lesion benign or malignant

• Signs of benign lesions– Well circumscribed, regular borders, slow

growth

• Signs of malignancy– Tissue destruction, irregular borders, loss of

normal anatomy– Around eye look for loss of lashes

Skin Lesions Management

• 5FU

• Imiquimod – immune response modifier – toll-like receptor 7 (TLR7) to stimulate

cytokines (IFN-α, TNF, IL-6)

• Surgical excision with margin control

What about Jack

• Type 1 Fitzpatrick skin type

• Melanoma (+ve family history)

• Possible metastatic SCC

• Fitness to drive

• Cataracts

• UV effects on the eye