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
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Opthalmology
Optalmology
Rhinoceros
Ophthalmology
55%
40%
2%
3%
Subspecialties
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Anterior Segment
Glaucoma
Uveitis
Neuroophthalmology
Paediatric Ophthalmology/Strabismus
Vitreo-Retinal
Ocular Adnexal
Ocular Pathology
Don’t wait for the planets to be
aligned
Opportunities
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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
10%
15%
15%
60%
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
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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
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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
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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
– SCC
– Melanoma
1700/year/100,000
600/year/100,000
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 instability
Inherited mutations are termed germline
Acquired mutations are termed somatic
Rarely tumours are hereditary
Most tumours are due to
Altered DNA replication
Carcinogens
Defects 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
Normal Epidermis
Langerhans Cells
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
cis-Urocanic acid
trans-Urocanic
acid
Abundant in stratum corneum
Converts to cis isomer with UV
Induces TNF α from keratinocytes
Non Langerhans
Inflammatory Cells
UV
TNF α
Further negative effect on LC
Alters morphology
Increases depletion from the epidermis
Inhibit Contact Hypersensitivity Reaction
(CHS)
Non Langerhans
Inflammatory Cells
UV
TNF α IL10
UV stimulates IL-10 production from
keratinocytes Main source is from
macrophages
Inhibits presentation of tumour Ag’s by APC
Non Langerhans
Inflammatory Cells
UV
TNF α IL10
Non Langerhans
Inflammatory Cells
Th1
UV
TNF α IL10
IL-12, IFN γ
Non Langerhans
Inflammatory Cells
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
Metastasis
Normal
Nevus
Dysplastic
RGP
VGP
Histological progression in
melanoma
Atypical Melanocytic hyperplasia
Level 1 melanoma RGP
Lentigo maligna
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
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Type 1 Fitzpatrick skin type
Melanoma (+ve family history)
Possible metastatic SCC
Fitness to drive
Cataracts
UV effects on the eye