UV and the Eye Timothy Sullivan Professor of Ophthalmology Glen Gole Professor of Ophthalmology University of Queensland
Mar 26, 2015
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