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

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Presentation on theme: "UV and the Eye Timothy Sullivan Professor of Ophthalmology Glen Gole Professor of Ophthalmology University of Queensland."— Presentation transcript:

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

2 Case Summary Jack –83 yo retired farmer –Past history precancerous lesions, NMSC, cataracts –Wants a drivers licence check

3 Ophthalmology The branch of medicine that deals with the anatomy, functions, pathology, and treatment of the eye Opthalmology55% Optalmology40% Rhinoceros2% Ophthalmology3%

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

5 Dont 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 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 60% 10% 15%

9 Australian Significance people are blind – by have low vision –1 million by 2020 –60% refractive –10% cataract –10% ARMD

10 Ophthalmohelioses Ocular Adnexae Ocular Surface Lens Uveal Tract Vitreous Retina Ocular Alignment Systemic

11 Ocular Adnexae

12 Ocular Surface Keratitis –Snow blindness Pterygium Ocular Surface Squamous Neoplasia Reactivation Herpes

13 Crystalline Lens Early Presbyopia Cataract Pseudoexfoliation Dysphotopsia

14 Uveal Tract Melanoma Pigment Dispersion Uveitis

15 Vitreoretinal Liquefaction Solar maculopathy Macular Degeneration

16 Systemic Melanoma NMSC Xeroderma Pigmentosa Basal cell nevus syndrome Photosensitivity

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 EOMs

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 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


24 Layers of the skin Thinnest skin on body Epidermis –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 –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 Langerhans Cells Normal Epidermis

33 UV Interferes with AG presentation with Langerhans Cells being the prime target Depletes Langerhans Cells Alters their dendritic morphological features Decreases expression of Class II MHC molecules (ICAM1)

34 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

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

36 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 Ags by APC

37 UV Non Langerhans Inflammatory Cells TNF α IL- 10 Th1

38 UV Non Langerhans Inflammatory Cells TNF α IL- 10 IL-12, IFN γ IL-4, IL-10 Th1Th2

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

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 Gorlins syndrome and sporadic BCCs 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 –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 Normal Nevus VGP Dysplastic RGP Metastasis

49 Histological progression in melanoma Atypical Melanocytic hyperplasiaLentigo maligna Level 1 melanoma RGPMelanoma 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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