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UV and the Eye Timothy Sullivan Professor of Ophthalmology Glen Gole

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1 UV and the Eye Timothy Sullivan Professor of Ophthalmology Glen Gole
University of Queensland

2 Case Summary Jack 83 yo retired farmer
Past history precancerous lesions, NMSC, cataracts Wants a driver’s licence check

3 Ophthalmology The branch of medicine that deals with the anatomy, functions, pathology, and treatment of the eye Opthalmology 55% Optalmology 40% Rhinoceros 2% Ophthalmology 3%

4 Subspecialties Anterior Segment Glaucoma Uveitis Neuroophthalmology
Paediatric Ophthalmology/Strabismus Vitreo-Retinal Ocular Adnexal Ocular Pathology

5 Don’t wait for the planets to be aligned

6 Opportunities Interested Clinicians Basic Science Researchers
Clinician Scientists Clinical Research Poor beaten wretches at the coal face of clinical practice

7 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

8 Causes of Blindness 10% 15% 15% 60% Infectious causes decreasing
Diabetic retinopathy increasing exponentially 15% 60%

9 Australian Significance
people are blind by 2020 have low vision 1 million by 2020 60% refractive 10% cataract 10% ARMD VanNewkirk MR, Weih LM, McCarty CA, Taylor HR. The cause-specific prevalence of bilateral visual impairment in Victoria, Australia - the Visual Impairment Project. Ophthalmology 2001; 108: <PubMed> Livingston PM, Carson CA, Stanislavsky YL, et al. Methods for a population-based study of eye disease: the Melbourne Visual Impairment Project. Ophthalmic Epidemiol 1994; 1: <PubMed> Attebo K, Mitchell P, Smith W. Visual acuity and the causes of visual loss in Australia. The Blue Mountains Eye Study. Ophthalmology 1996; 103:

10 Ophthalmohelioses Ocular Adnexae Ocular Surface Lens Uveal Tract
Vitreous Retina Ocular Alignment Systemic Sun, eye, ophthalmohelioses and the contact lens, Minas Coroneo, Accuvue Eye Health Advisor Johnson & Johnson

11 Ocular Adnexae

12 Ocular Surface Keratitis Pterygium Ocular Surface Squamous Neoplasia
Snow blindness Pterygium Ocular Surface Squamous Neoplasia Reactivation Herpes Vernal catarrh, pinguecula, pterygium, climatic keratopathy (Labrador keratopathy), actinic granuloma, keratitis (flash, snow blindness), arcus/transparency, band keratopathy, corneal endothelial polymorphism, reactivation of herpetic keratitis, scleritis in porphyria, senile scleral plaques, post photorefractive keratectomy (PRK) haze, malignancy of the cornea or conjunctiva

13 Crystalline Lens Early Presbyopia Cataract Pseudoexfoliation
Dysphotopsia

14 Uveal Tract Melanoma Pigment Dispersion Uveitis

15 Vitreoretinal Liquefaction Solar maculopathy Macular Degeneration
Geographic dry ARMD, Wet choroidal NVM with leakage on FFA

16 Systemic Melanoma NMSC Xeroderma Pigmentosa Basal cell nevus syndrome
Photosensitivity Xeroderma pigmentosum, basal cell carcinoma, basal cell nevus syndrome, porphyria cutanea tarda, polymorphous light eruption, drug-induced photosensitivity, uremia, immunosuppression, myopia Table 1. A list of the ophthalmohelioses. Figure 1. Peak ocular exposures were recorded during

17 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 Most ophthalmic conditions (at least their anatomic location) can be diagnosed from history alone

18 History Specific Complaints Pain
Foreign body sensation, ache, photophobia, referred pain Redness Eye, eyelid, unilateral, bilateral , other symptoms.

19 Visual Symptoms REMEMBER RED EYE + PAIN IS NOT CONJUNCTIVITIS
Beware of discharge, pus,watery eyes Itch Burning stinging dryness

20 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

21 Visual Symptoms Night blindness Colour Vision Visual Phenomena
Spots, scotomata, flashes floaters, halos Visual distortion Micropsia, macropsia, metamorphopsia Ptosis Gradual, sudden

22 Background Incidence of skin cancer in Queensland is the highest in the world BCC /year/100,000 SCC /year/100,000 Melanoma /year/100,000 United States 800,000 BCC/year 200,000 SCC/year 53,000 Melanoma/year Basal cell carcinomas represent 90% of all eyelid malignancies,. The incidence of basal cell carcinoma in Queensland is the highest in the world, and as such it is seen commonly in tertiary oculoplastics practice in SEQ. The best treatment is prevention, but when this fails, definitive management is surgical. Lesions are excised with adequate histological excision margins to prevent local recurrence.

23

24 Layers of the skin Thinnest skin on body Epidermis Dermis
BCC basal layer SCC more superficial MM usually basal Dermis

25 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

26 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

27 Skin Cancer Two broad classes of genes contribute to cancer Oncogenes
Tumour suppressor genes

28 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

29 Skin Cancer Tumour suppressor genes Gatekeeper genes Caretaker 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)

30 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

31 Local Immunosuppression
UV induces an environment of local immunosuppression

32 Normal Epidermis Langerhans Cells
UV induces an environment of local immunosuppression, Normal epidermis has a resting population of Langerhans Cells.

33 Depletes Langerhan’s 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 induced immunosuppression 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)

34 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

35 UV TNF α Further negative effect on LC Alters morphology Increases depletion from the epidermis Inhibit Contact Hypersensitivity Reaction (CHS) Non Langerhans Inflammatory Cells

36 Inhibits presentation of tumour Ag’s by APC
UV TNF α IL-10 UV stimulates IL-10 production from keratinocytes Main source is from macrophages Inhibits presentation of tumour Ag’s by APC IL-10 produced by many cells types. UV stimulates IL-10 production from keratinocytes Main source is from macrophages Inhibits presentation of tumour Ag’s by APC Non Langerhans Inflammatory Cells

37 Non Langerhans Inflammatory Cells
UV TNF α IL-10 IL-10 produced by many cells types. UV stimulates IL-10 production from keratinocytes Main source is from macrophages Inhibits presentation of tumour Ag’s by APC Non Langerhans Inflammatory Cells Th1

38 IL-12, IFN γ IL-4, IL-10 UV TNF α IL-10
IL-10 produced by many cells types. UV stimulates IL-10 production from keratinocytes Main source is from macrophages Inhibits presentation of tumour Ag’s by APC IL-12, IFN γ Non Langerhans Inflammatory Cells IL-4, IL-10 Th1 Th2

39 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 IL-10 produced by many cells types. UV stimulates IL-10 production from keratinocytes Main source is from macrophages Inhibits presentation of tumour Ag’s by APC

40 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

41 BCC Aetiology No “promotion stage”
Involves mutations of the PATCHED gene Human homologue of a Drosophila gene UV B is the major carcinogen

42 Hedgehog/patched/smoothened/Gli pathway
Mutations in PTCH causes Gorlin’s syndrome and sporadic BCC’s 9q22.3

43 Multistage Model of Carcinogenesis
SCC conforms to this model Precursor lesions acquire successive genetic lesions p53 clones Actinic keratosis Intraepidermal carcinmoma Invasive SCC Metastasis

44 Melanoma Aetiology Intermittent intense sun exposure Nevi
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

45 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

46 Genetic changes in Melanoma
UV signature mutations rare in melanoma P53 unlikely to play a major role in melanoma

47 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)

48 Melanoma Linear Tumour Progression Model
Metastasis Normal RGP Nevus Dysplastic VGP

49 Histological progression in melanoma
Atypical Melanocytic hyperplasia Lentigo maligna Upper left Atypical Melanocytic hyperplasia, Get a Progressive centrifugal spread of a flat pigmented area with Intraepidermal proliferation of atypical melanocytes which Precedes the vertical growth phase Seen in LMM, SSM, and Acral lentiginous melanoma Upper right definite HMF or lentigo maligna. Lower left Definite level 1 melanoma with nesting and severe atypia. Remember has a horizontal growth phase and ( Lower right) Vertical growth phase melanoma Characterised by dermal invasion, Epithelioid, spindle or nevoid melanoma cells which Vary in size or shape Nodular melanoma has No radial growth phase with Dermal invasion present from outset, Clinically palpable from outset Level 1 melanoma RGP Melanoma VGP

50 Sebaceous Carcinoma

51 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

52 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

53 What about Jack Type 1 Fitzpatrick skin type
Melanoma (+ve family history) Possible metastatic SCC Fitness to drive Cataracts UV effects on the eye


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