The Eye is full of pathological diseases.

Awesome presentation

1. The Eye Balcha D. (MD, Pathologist)

2. Orbit Inflammatory Conditions Graves’ Disease Neoplasms Eyelid Conjunctiva Conjunctival Scarring Pinguecula & Pterygium Neoplasms Sclera Cornea Keratitis & Ulcers Degenerations & Dystrophies Anterior Segment Cataract Glaucoma Endophthalmitis & Panophthalmitis Uvea Uveitis Neoplasms Retina and Vitreous Detachment Vascular Disease Retinopathy of Prematurity Degeneration Retinitis Neoplasms Optic Nerve Anterior Ischemic Optic Neuropathy Papilledema Glaucomatous Optic Nerve Damage Neuritis The End-Stage Eye: Phthisis Bulbi

3. Introduction

4. Orbit The orbit is a compartment closed medially, laterally, and posteriorly. Diseases causing increased orbital contents lead to proptosis (forward displacement of the eye).

5. Proptosis Anterior displacement of the eye Types of Proptosis Axial Proptosis: Eye bulges directly forward. Examples: Masses within the cone formed by horizontal rectus muscles. Optic nerve tumors (glioma, meningioma). Positional Proptosis: Eye displaced in a specific direction. Example: Enlargement of the lacrimal gland causing inferior and medial displacement.  disrupt the tear film  corneal exposure to air  pain, ulceration & infection

6. Inflammatory Conditions Systemic ( Wegener granulomatosis ) Local extension (uncontrolled sinus infection) Sinus-Related Infections: Spread to the orbit as acute bacterial or fungal infections. Common in immunosuppressed individuals or those with diabetic ketoacidosis. Granulomatosis with polyangiitis may involve the orbit secondarily from sinus extension. Idiopathic Orbital Inflammation: Also known as orbital inflammatory pseudotumor. Can affect various orbital tissue elements: Lacrimal gland (sclerosing dacryoadenitis). Extraocular muscles (orbital myositis). Tenon capsule (posterior scleritis). Rule out IgG4-related disease before diagnosing idiopathic orbital inflammation.

7. In idiopathic orbital inflammation (orbital inflammatory pseudotumor) the orbital fat is replaced by fibrosis. Note the chronic inflammation, accompanied in this case by eosinophils.

8. Thyroid Ophthalmopathy (Graves’ Disease) Proptosis in Graves’ disease: Accumulation of extracellular matrix proteins and fibrosis in rectus muscles. Can occur independently of thyroid function. Morphology and Histological Features Idiopathic Orbital Inflammation: Histological features: Chronic inflammation. Variable fibrosis. Inflammatory infiltrate (lymphocytes, plasma cells, eosinophils). Germinal centers indicate reactive lymphoid hyperplasia. Presence of vasculitis suggests an underlying systemic condition. Necrosis, degenerating collagen, and vasculitis raise suspicion of granulomatosis with polyangiitis. Idiopathic orbital inflammation can be confined to the orbit or coexist with sclerosing inflammation in other regions.

9. The extraocular muscles are greatly distended in this postmortem dissection of tissues from a patient with thyroid (Graves) ophthalmopathy. Note that the tendons of the muscles are spared.

10. Neoplasms Most frequently encountered primary neoplasms of the orbit are vascular in origin: Capillary hemangioma of infancy and early childhood. Lymphangioma (both unencapsulated). Encapsulated cavernous hemangioma (typically in adults). Encapsulated orbital masses: Pleomorphic adenoma of the lacrimal gland. Dermoid cyst. Neurilemmoma. Non-Hodgkin lymphoma: Can affect the entire orbit or be confined to specific compartments (e.g., lacrimal gland). Classified according to the World Health Organization (WHO) system. Primary orbital malignancies: Arise from various orbital tissues. Classified according to the classification system of the parent tissue. Example: Tumors of the lacrimal gland are classified as salivary gland tumors. Metastases to the orbit: May present with distinctive signs and symptoms indicating the origin of the tumor. Examples: Metastatic prostatic carcinoma may mimic idiopathic orbital inflammation. Metastatic neuroblastoma and Wilms tumor (richly vascular neoplasms) may cause periocular ecchymoses. Neoplasms may invade the orbit from the sinuses.

11. Eyelid Functional Anatomy: Eyelid composed of external skin and mucosa (conjunctiva) facing the eye. Eyelid functions include covering, protecting the eye, and tear film production. Chronic inflammation (blepharitis) or neoplasms can obstruct sebaceous gland drainage, leading to lipid extravasation and granulomatous response (lipogranuloma or chalazion).

12. Neoplasms Basal cell carcinoma: Predominant malignancy of the eyelid. Prompt treatment is crucial to preserve vision due to potential corneal damage from incomplete eyelid closure. Basal cell carcinoma has a higher occurrence in the lower eyelid and medial canthus. Sebaceous Carcinoma: May mimic chalazion or present as diffuse eyelid thickening. Resembles inflammatory processes like blepharitis or ocular cicatricial pemphigoid. Intraepithelial spread is observed, similar to Paget disease. Tends to spread to parotid and submandibular nodes. Mortality rate can be as high as 22%. Less likely associated with Muir-Torre syndrome compared to sebaceous neoplasms in other locations. Morphology: Vacuolization of cytoplasm aids in the diagnosis of moderately differentiated or well-differentiated sebaceous carcinoma. Histologically resembles other malignancies, such as basal cell carcinoma, making accurate diagnosis challenging. Pagetoid spread may mimic Bowenoid actinic keratosis or carcinoma in situ. Sebaceous carcinoma can spread through conjunctival epithelium, epidermis, lacrimal drainage system, nasopharynx, and lacrimal gland ductules.  Kaposi Sarcoma: Can develop in the eyelid or conjunctiva, particularly in individuals with AIDS. Appears purple in the dermis of the eyelid and bright red in the thin mucous membrane of the conjunctiva. Differential diagnosis includes subconjunctival hemorrhage due to its clinical appearance.

13. Pagetoid spread of sebaceous carcinoma. Neoplastic cells with foamy cytoplasm are present within the epidermis (arrow). Invasive sebaceous carcinoma was identified elsewhere in this biopsy sample.

14. Conjunctiva Functional Anatomy Palpebral conjunctiva Tightly tethered to the tarsus and can form minute papillary folds in response to inflammation (e.g., allergic conjunctivitis, bacterial conjunctivitis). Fornix Pseudostratified columnar epithelium rich in goblet cells. Contains accessory lacrimal tissue and ductules of the main lacrimal gland. Viral conjunctivitis can cause lymphoid follicles to enlarge visibly during slit-lamp examination. Nondirected conjunctival biopsy in suspected sarcoidosis may yield granulomas in the fornix (up to 50% yield). Bulbar conjunctiva Nonkeratinizing stratified squamous epithelium covering the surface of the eye. The limbus marks the transition between conjunctival and corneal epithelium. Lymphatic channels and regional lymph nodes Malignant neoplasms arising in the eyelid and conjunctiva tend to spread to regional lymph nodes, including the parotid and submandibular node groups.

15. Conjunctival Scarring Causes Infection with Chlamydia trachomatis (trachoma) can lead to significant conjunctival scarring. Caustic alkalis exposure or ocular cicatricial pemphigoid can also result in conjunctival scarring. Consequences Scarring can lead to a decrease in the number of goblet cells, which produce mucin essential for tear adherence to the corneal epithelium. Conjunctival scarring can result in a painful dry eye and compromised vision. Dry eye can also occur due to a deficiency in the aqueous component of the tear film generated by accessory lacrimal glands embedded within the eyelid and fornix.

16. Pinguecula & Pterygium Submucosal elevations on the conjunctiva. Result from actinic (sun) damage. Located in the sun-exposed regions of the conjunctiva (interpalpebral fissure (between the upper and lower eyelids)). Pterygium: Arises from the conjunctiva astride the limbus (the border between the cornea and the sclera). Submucosal growth of fibrovascular connective tissue. Can migrate onto the cornea, dissecting into the plane occupied normally by the Bowman layer (a layer within the cornea). Pterygium does not cross the pupillary axis (the line passing through the center of the pupil). Typically, does not pose a threat to vision. Possibility of inducing mild astigmatism due to corneal distortion. Most pterygia are benign; however, submitting the excised tissue for pathological examination is recommended. In rare cases, precursors of actinic-induced neoplasms, such as squamous cell carcinoma and melanoma, can be detected in pterygium lesions. Pinguecula: Appears astride the limbus (the border between the cornea and the sclera). Small, yellowish submucosal elevation. Remains confined to the conjunctiva without extending onto the cornea. Typically, benign and does not pose a threat to vision.

17. Neoplasms Squamous Neoplasms Conjunctival squamous cell carcinoma may be preceded by intraepithelial neoplastic changes designated as ocular surface squamous neoplasia. Squamous papillomas and conjunctival intraepithelial neoplasia may be associated with human papillomavirus types 16 and 18. Conjunctival Nevi Commonly encountered but seldom invade the cornea or appear in the fornix or over the palpebral conjunctiva. Pigmented lesions in these zones may represent melanomas or melanoma precursors. Compound nevi of the conjunctiva contain subepithelial cysts lined by surface epithelium. Inflamed juvenile nevus, characterized by inflammation rich in lymphocytes, plasma cells, and eosinophils, is completely benign. Conjunctival Melanomas Unilateral neoplasms typically affecting fair-complexioned individuals in middle age. Development often through a phase of intraepithelial growth called primary acquired melanosis with atypia or conjunctival melanocytic intraepithelial neoplasia (C-MIN). Incompletely treated primary acquired melanosis with atypia has a high risk of progressing to conjunctival melanoma. BRAF V600 mutations may be identified in nearly 40% of conjunctival melanomas. Prevention through extirpation of precursor lesions is the best approach. Lesions tend to spread first to the parotid or submandibular lymph nodes. Approximately 25% of conjunctival melanomas are fatal.

18. (A, B) Cystic compound nevus of the conjunctiva. (C, D) Conjunctival malignant melanoma. In C, note the deflection of the beam of the slit lamp over the surface of the lesion, indicative of invasion. (A, B, Benign conjunctival melanocytic lesions: clinicopathologic features,

19. Sclera Composition and Healing Mainly consists of collagen and contains few blood vessels and fibroblasts. Wounds and surgical incisions in the sclera tend to heal poorly due to the limited blood supply and fibroblast presence. Immune complex deposits in the sclera, such as in rheumatoid arthritis, can lead to necrotizing scleritis. " Blue" Appearance of the Sclera Thin sclera following episodes of scleritis can cause the normally brown color of the uvea to appear blue clinically due to the optical Tyndall effect. Exceptionally high intraocular pressure can cause thinning of the sclera, and when lined by uveal tissue, it forms a lesion called a staphyloma, which also appears blue. Sclera may appear blue in osteogenesis imperfecta. Heavily pigmented congenital nevus of the underlying uvea can cause the sclera to appear blue, known as congenital melanosis oculi. When accompanied by periocular cutaneous pigmentation, the condition is known as nevus of Ota.

20. Cornea Functional Anatomy Refractive Surface The cornea and its overlying tear film, not the lens, constitute the major refractive surface of the eye. Myopia (nearsightedness) is typically caused by the eye being too long for its refractive power. Hyperopia (farsightedness) results from an eye that is too short. Corneal shape plays a significant role in the refractive properties of the eye, as evidenced by procedures like LASIK that modify corneal shape. Anterior Cornea Covered by epithelium resting on a basement membrane. The acellular Bowman layer lies beneath the epithelial basement membrane and acts as a barrier against malignant cell penetration into the stroma. Corneal Stroma Lacks blood vessels and lymphatics, contributing to corneal transparency. Nonimmunologic graft failure is more common than immunologic graft rejection in corneal transplantation. Precise collagen alignment in the stroma contributes to transparency. Corneal vascularization can occur with chronic corneal edema, inflammation, and scarring. Topical VEGF antagonists show promise in preventing corneal vascularization. Scarring and edema disrupt the spatial alignment of stromal collagen and lead to corneal opacification. Corneal Endothelium Derived from neural crest, not vascular endothelium. Rests on Descemet membrane, its basement membrane. Decreased endothelial cells or malfunction can lead to stromal edema and bullous keratopathy. Descemet membrane thickens with age. Site of copper deposition in the Kayser-Fleischer ring of Wilson disease

21. The inset at the upper left is anterior layers of the cornea: epithelium (e), Bowman layer (b), and stroma (s). A very thin PAS-positive basement membrane separates the epithelium from the Bowman layer. Note that the Bowman layer is acellular. The inset at the lower right is Descemet membrane and the corneal endothelium. The “holes” in the stroma are artifactitious spaces between parallel collagenous stromal lamellae.

22. Keratitis & Ulcers Pathogens causing corneal ulceration: Bacterial: Various bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa, can cause corneal ulcers. Fungal: Fungal infections, including those caused by Candida species or Aspergillus species, can lead to corneal ulceration. Viral (especially herpes simplex and herpes zoster): Herpes simplex virus (HSV) and herpes zoster virus (HZV) are common causes of viral keratitis leading to corneal ulcers. Protozoal (Acanthamoeba): Acanthamoeba keratitis is a rare but serious infection caused by Acanthamoeba species. Activation of collagenases within corneal epithelium and stromal fibroblasts can lead to the breakdown of collagen fibers in the corneal stroma, contributing to the ulceration process. Clinical features: Hypopyon: Accumulation of exudate and inflammatory cells in the anterior chamber, which is visible as a layered collection at the bottom of the anterior chamber. Slit-lamp examination: A specialized microscope used to examine the cornea, enabling visualization of the ulcer and associated inflammation. Hypopyon seldom contains organisms: While the corneal ulcer may be infectious, the hypopyon typically lacks visible organisms and primarily represents the vascular response to acute inflammation. Distinctive features of specific keratitis types: E.g. Chronic herpes simplex keratitis: Can lead to a granulomatous reaction affecting the Descemet membrane, a component of the cornea's endothelial layer .

23. Chronic herpes simplex keratitis. The cornea is thin and scarred (note the increased number of fibroblast nuclei). Granulomatous reaction in the Descemet membrane, illustrated in this photomicrograph (arrows), is a histologic hallmark of chronic herpes simplex keratitis.

24. Corneal Degenerations & Dystrophies Degenerations: Corneal degenerations typically occur sporadically and are not inherited. Degenerations can affect either one or both eyes. Examples: Calcific band keratopathy: Calcium deposition in the Bowman layer: Chronic uveitis, especially in individuals with chronic juvenile rheumatoid arthritis, may lead to the deposition of calcium in the Bowman layer of the cornea. Actinic band keratopathy: Solar elastosis in superficial corneal collagen due to chronic UV exposure: High levels of ultraviolet (UV) light exposure over time can cause solar elastosis, or degenerative changes, in the superficial layers of corneal collagen. Dystrophies: Corneal dystrophies have a genetic basis and can be inherited. Dystrophies typically affect both eyes. Different types of corneal dystrophies can impact specific layers of the cornea or involve multiple layers simultaneously We will discuss Keratoconus Fuchs Endothelial Dystrophy Stromal Dystrophies

25. Keratoconus Keratoconus is a relatively common disorder with an incidence of approximately 1 in 2000 individuals. Characteristics: Keratoconus is characterized by the gradual thinning and bulging of the cornea, leading to a conical shape. Unlike in infections or inflammatory conditions, keratoconus does not involve inflammation or blood vessel growth in the cornea. The cornea develops a protruding, cone-like shape, which causes irregular astigmatism and visual distortion. Associations: Down syndrome: Individuals with Down syndrome have a higher prevalence of keratoconus compared to the general population. Marfan syndrome: Keratoconus is also associated with Marfan syndrome, a genetic disorder that affects connective tissues. Atopic disorders: The presence of atopic conditions such as allergic rhinitis or asthma may increase the risk of developing keratoconus.

26. Cont…. Morphology: Thinning of the cornea: Particularly in the central or inferior region. Breaks or irregularities in the Bowman layer: Descemet membrane rupture: Corneal hydrops (sudden effusion of aqueous humor): The weakened cornea in keratoconus can lead to the sudden bulging and fluid accumulation within the cornea, causing corneal hydrops. Corneal scarring: Over time, corneal scarring can occur as a result of the thinning, stretching, and structural changes in the cornea. Treatment options: Rigid contact lenses: Specialized rigid gas permeable contact lenses are often used to provide a smooth, regular surface for the cornea, improving vision and reducing astigmatism. Corneal transplantation: In severe cases where visual impairment cannot be corrected with contact lenses, a corneal transplant (keratoplasty) may be recommended to replace the thin and distorted cornea with a healthy donor cornea.

27. Cont…. Complications: Acute corneal hydrops: Corneal hydrops can cause sudden vision loss and may require urgent treatment to manage the condition and minimize scarring. Descemet membrane ruptures due to high intraocular pressure or obstetric forceps injury: In some cases, increased intraocular pressure or trauma, such as forceps injury during childbirth, can lead to Descemet membrane ruptures, further complicating the condition.

28. Fuchs Endothelial Dystrophy Type of corneal dystrophy characterized by loss of endothelial cells and resulting edema and stromal thickening. Principal indication for corneal transplantation in the United States. Clinical Manifestations: Stromal Edema: Decrease in total number of endothelial cells. Residual endothelial cells unable to maintain stromal deturgescence. Edema and thickening of the corneal stroma. Ground-glass appearance clinically. Blurred vision. Bullous Keratopathy: Result of primary loss of endothelial cells. Chronic edema leading to stromal vascularization. Common indication for corneal transplantation. Early Disease Stage: Endothelial Cell Activity: Drop-like deposits of abnormal basement membrane material (guttata). Detectable with slit-lamp examination. Pseudophakic Bullous Keratopathy: Definition: Endothelial cell decreases following cataract surgery. Can occur in individuals without early signs of Fuchs dystrophy. Common Indication for Corneal Transplantation.

29. Fuchs dystrophy.

30. Anterior Segment Functional Anatomy

31. Cataract The term cataract describes lenticular opacities that may be congenital or acquired. Which affect vision and lead to visual impairment if left untreated. Causes of Cataract: Systemic diseases associated with cataract: Galactosemia Diabetes mellitus Wilson disease Atopic dermatitis Drugs: Prolonged use of corticosteroid medications, such as prednisone, can increase the risk of cataract formation. Radiation: Exposure to high levels of radiation, such as during cancer treatment, can cause cataracts. Trauma: Eye injuries, including blunt trauma or penetrating injuries, can lead to the development of cataracts. Intraocular disorders: Various eye conditions, such as glaucoma, uveitis, or retinitis pigmentosa, can be associated with cataract formation.

32. Cataract Age-Related Cataract: Age-related cataract is the most common type of cataract and typically occurs due to natural aging processes. It results from the opacification of the lens nucleus, a process known as nuclear sclerosis. The accumulation of urochrome pigment within the lens nucleus may cause a brown discoloration, leading to a distortion in the perception of blue colors. The prevalence of nuclear sclerotic cataracts is higher in older individuals. The impact of nuclear sclerotic cataracts on color vision is often compared to the predominance of yellow hues seen in Rembrandt's paintings in his later life. Physical changes in the lens can lead to different types of cataracts: Lens cortex liquefaction: The cortex, the outer layer of the lens, may become liquefied, leading to the formation of cortical cataracts. Migration of lens epithelium: The lens epithelium, the layer of cells covering the lens, can migrate posteriorly to the lens equator, causing posterior subcapsular cataracts. Cataract Treatment: The most common technique for cataract removal is phacoemulsification: Phacoemulsification involves using ultrasound energy to break up the opacified lens into tiny fragments, which are then removed from the eye. The lens capsule, the transparent membrane that surrounds the lens, is typically left intact. After removing the lens contents, a prosthetic intraocular lens (IOL) is usually implanted to restore vision. The choice of IOL depends on various factors, including the patient's visual needs, lifestyle, and any pre-existing ocular conditions. Different types of IOLs include monofocal , multifocal, and toric lenses.

33. Glaucoma Definition of Glaucoma: Glaucoma: Collection of diseases with distinctive changes in visual field and optic nerve cupping. Most glaucoma’s associated with elevated intraocular pressure (IOP). Normal or low-tension glaucoma can occur with normal IOP. Pathophysiology of Glaucoma: Aqueous humor: Produced in ciliary body, passes through pupil to anterior chamber. Drainage pathway: Trabecular meshwork in angle between corneal periphery and anterior iris. Elevation in IOP: Increased resistance to aqueous outflow in open-angle glaucoma.

34. Glaucoma cont … Classification of Glaucoma: Open-angle glaucoma: Aqueous humor has complete access to trabecular meshwork. Subtypes: Primary open-angle glaucoma: Angle is open, minimal structural changes. Secondary open-angle glaucoma: Various causes affect aqueous outflow. Angle-closure glaucoma: Peripheral iris adheres to trabecular meshwork, obstructing outflow. Subtypes: Primary angle-closure glaucoma: Shallow anterior chambers, often hyperopia. Secondary angle-closure glaucoma: Caused by pathologic membranes or iris compression. Complications of Glaucoma: Primary angle-closure glaucoma: Iris bombé : Bowing of iris periphery due to elevated pressure. Anterior subcapsular opacities: Minute lens epithelial opacities. Corneal edema and bullous keratopathy: Result of prolonged elevated IOP. Secondary angle-closure glaucoma: Causes: Contraction of pathologic membranes on iris. Neovascularization from retinal ischemia or tumors. Mechanical compression of iris by ciliary body tumors

35. Intraocular inflammation: Endophthalmitis & Panophthalmitis Intraocular inflammation: Leaky vessels in the ciliary body and iris Accumulation of cells and exudate in the anterior chamber Visualized with a slit lamp Keratic precipitates may form on corneal endothelium Size and shape can provide clues to underlying cause "Mutton-fat" keratic precipitates in sarcoidosis Exudate leads to adhesions between structures Anterior synechiae: Iris and trabecular meshwork or cornea Can cause increased intraocular pressure and optic nerve damage Posterior synechiae: Iris and anterior surface of the lens Prolonged contact can induce fibrous metaplasia of lens epithelium (anterior subcapsular cataract)

36. IOI: Endophthalmitis & Panophthalmitis Endophthalmitis: Inflammation within the vitreous humor Poorly tolerated by the retina Classified as: Exogenous: Originates from the environment through a wound Endogenous: Delivered hematogenously Panophthalmitis: Inflammation involving retina, choroid, and sclera Extends into the orbit Represents severe intraocular and orbital inflammation

37. Uvea Consists of the iris, choroid, and ciliary body. The iris regulates the amount of light entering the eye. The choroid provides oxygen and nutrients to the retina. The ciliary body produces aqueous humor.

38. Uveitis Inflammation in one or more uveal tissues. Can involve the iris (iritis), ciliary body (cyclitis), or choroid (choroiditis). May result from infections, autoimmune disorders, or systemic diseases. Uveitis can lead to complications in the posterior segment of the eye. Inflammation in the uvea can affect the retina, optic nerve, and vitreous. Retinal pathology is commonly associated with uveitis . Causes of Uveitis: Infectious agents: Bacterial (e.g., syphilis, tuberculosis). Viral (e.g., herpes simplex, cytomegalovirus). Fungal (e.g., histoplasmosis, candidiasis). Autoimmune disorders: Rheumatoid arthritis, systemic lupus erythematosus. Systemic diseases: Sarcoidosis, Behçet's disease, Vogt-Koyanagi-Harada syndrome. Granulomatous Uveitis : Sympathetic Ophthalmia: Noninfectious uveitis limited to the eye. Occurs following penetrating eye injury or surgery. Delayed hypersensitivity reaction to self-antigens. Bilateral granulomatous inflammation ( panuveitis ). Diagnosis: Ophthalmic examination, imaging. Histopathological analysis after enucleation. Treatment: Systemic immunosuppressive agents (corticosteroids, immunomodulators).

39. Sympathetic ophthalmia. The granulomatous inflammation depicted here was identified diffusely throughout the uvea. The uveal granulomas may contain melanin pigment and may be accompanied by eosinophils.

40. Neoplasms The most common intraocular malignancy of adults is metastasis to the uvea, typically to the choroid. Asst’d w/ Extremely short survival Tx is usually by radiotherapy, is palliative

41. Uveal Nevi and Melanomas Uveal Melanoma Most common primary intraocular malignancy in adults Accounts for approximately 5% of all melanomas in the US Age-adjusted incidence: 5.1 per 1 million per year Arises from melanocytes within the uvea (choroid, ciliary body, iris) Wide range of presentations, including pigmented or non-pigmented lesions Diagnosis: Ophthalmic examination, imaging studies, occasional biopsy Uveal Nevi Relatively common benign intraocular lesions Choroidal nevi affect approximately 5% of the Caucasian population Arise from the proliferation of melanocytes Most nevi remain stable and do not progress to malignancy Regular monitoring by an ophthalmologist recommended

42. Uveal Nevi and Melanomas Epidemiology and Pathogenesis Stable Occurrence Uveal melanoma incidence remains stable over the years No clear correlation with ultraviolet (UV) light exposure Other factors, genetic predisposition, and environmental exposures may contribute Molecular Pathogenesis Distinct genetic and molecular characteristics from cutaneous melanoma Rare BRAF mutations in uveal melanoma Predominant oncogenic mutations: GNAQ and GNA11 (G protein-coupled receptors) Approximately 85% of uveal melanomas harbor gain-of-function mutations in GNAQ or GNA11 Activation of MAPK pathway and downstream proliferative signaling

43. Uveal Nevi and Melanomas Morphology Histological Types: Uveal melanomas can contain two types of cells: spindle and epithelioid. Spindle cells: Fusiform in shape. Epithelioid cells: Spherical with greater cytologic atypicality. Tumor-infiltrating lymphocytes may be present in some cases. Looping slit-like spaces lined by laminin surround tumor cell packets. These spaces serve as extravascular conduits for plasma and potentially blood transport. Unusual growth patterns promoted by tumor cells through vasculogenic mimicry. Hematogenous Spread: Uveal melanomas predominantly spread via hematogenous route. Exception: Rare cases of melanoma spreading through the sclera and invading conjunctiva, gaining access to conjunctival lymphatics.

44. Uveal Nevi and Melanomas Clinical Features Presentation : Most uveal melanomas are incidental findings or present with visual symptoms. Visual symptoms may be related to retinal detachment or glaucoma. Prognostic Factors: Size: Adverse outcome associated with larger lateral extent of the tumor. Cell type: Tumors with epithelioid cells have a worse prognosis than those with only spindle cells. Proliferative index: Higher index may indicate a poorer prognosis. Cytogenetic profiles (e.g., monosomy 3) and gene expression profiling can help stratify patients with different risks of metastatic disease. Treatment and Survival: No significant difference in survival between enucleation (removal of the eye) and eye-sparing radiotherapy. Melanomas in the iris tend to have a relatively indolent course. Melanomas in the ciliary body and choroid are more aggressive. 5-year survival rate is approximately 80%, but cumulative melanoma mortality rate is 40% at 10 years, increasing 1% per year thereafter. Metastases may occur many years after treatment, suggesting tumor dormancy. Targeted therapies, such as MAPK inhibitors, show some promising responses in clinical trials, but there is currently no effective treatment for metastatic uveal melanoma.

45. Uveal melanoma. (A) Fundus photograph from an individual with a relatively flat pigmented lesion of the choroid near the optic disc. (B) Fundus photograph of the same individual several years later; the tumor has grown and has ruptured through the Bruch membrane.

46. C) Gross photograph of a choroidal melanoma that has ruptured the Bruch membrane. The overlying retina is detached. D) Epithelioid melanoma cells associated with an adverse outcome.

47. Mid-lecture Break!

48. Retina

49. Retinal Detachment Separation of the neurosensory retina from the RPE Classification Rhegmatogenous RD Full-thickness retinal defect or tear present Retinal tears develop after vitreous collapse and traction by the posterior hyaloid Liquefied vitreous seeps through the tear, creating a space between neurosensory retina and RPE Surgical procedures: Scleral buckling, vitrectomy Complications: Proliferative vitreoretinopathy Nonrhegmatogenous RD No retinal break present Associated with retinal vascular disorders and RPE damage Fluid leakage from choroidal circulation under the retina Examples: Choroidal tumors, malignant hypertension

50. Retinal Vascular Disease: Hypertension Normally, the thin walls of retinal arterioles permit a direct visualization of the circulating blood by ophthalmoscopy. Retinal Arteriolosclerosis: Thickened arteriolar walls alter ophthalmic perception of circulating blood. Narrowed vessels, change in color of blood column (bright red to copper to silver) based on vascular wall thickness. Compression of retinal veins by arterioles at crossing points due to shared adventitial sheath. Venous stasis distal to arteriovenous crossing can lead to retinal vein branch occlusions. Malignant Hypertension: Damage to retinal and choroidal vessels. Choroidal vessel damage can result in focal choroidal infarcts (Elschnig spots). Damage to choriocapillaris affects overlying RPE, leading to exudate accumulation and retinal detachment. Exudate from damaged retinal arterioles accumulates in the outer plexiform layer (macular star). Retinal arteriolar occlusion can cause nerve fiber layer infarcts, seen as cotton-wool spots. Cotton-wool spots result from interrupted axoplasmic transport and accumulation of mitochondria ( cytoid bodies).

51. The retina in hypertension. The wall of the retinal arteriole (arrow) is thick. Note the exudate (e) in the retinal outer plexiform layer. The fundus in hypertension.

52. Nerve fiber layer infarct. A “cotton-wool spot” is illustrated in the inset, adjacent to a flame-shaped (nerve fiber layer) hemorrhage. The histology of a cotton-wool spot—an infarct of the nerve fiber layer of theretina —is illustrated in the photomicrograph.

53. Diabetes Mellitus Retinal Microangiopathy: Eye profoundly affected by diabetes mellitus. Thickening of basement membrane of ciliary body epithelium is a histologic marker. Focus on retinal microangiopathy associated with diabetes mellitus. Prototype for understanding other retinal microangiopathies. Morphology: Nonproliferative Diabetic Retinopathy: Structural and functional abnormalities of retinal vessels beneath the internal limiting membrane. Thickening of retinal blood vessel basement membrane. Decreased pericytes relative to endothelial cells. Microaneurysms and retinal microhemorrhages. Physiological breakdown of blood-retinal barrier, leading to macular edema. Exudates accumulating in the outer plexiform layer. Hyperpermeability and micro-occlusions in the retinal microcirculation. Nonperfusion of the retina associated with upregulation of VEGF and intraretinal angiogenesis.

54. Diabetes Mellitus: cont … Proliferative Diabetic Retinopathy: New vessel formation on the surface of the optic nerve head or retina. Retinal neovascularization when vessels breach the internal limiting membrane. Quantity and location of neovascularization guide treatment. Neovascular membrane composed of angiogenic vessels with or without a supportive fibrous or glial stroma. Neovascular membranes extend along the potential plane between the internal limiting membrane and the posterior hyaloid. Posterior vitreous detachment may cause massive hemorrhage and scarring of the neovascular membrane. Scarring may wrinkle the retina, disrupt photoreceptor orientation, and cause traction retinal detachment. Traction retinal detachment can progress from nonrhegmatogenous to traction rhegmatogenous detachment. Neovascular Glaucoma: Development of neovascular membrane on the iris surface. Increased VEGF levels in the aqueous humor. Contraction of iris neovascular membrane leads to adhesions with trabecular meshwork. Anterior synechiae formation occludes aqueous outflow pathway. Contributes to elevated intraocular pressure (neovascular glaucoma).

55. The ciliary body in chronic diabetes mellitus, periodic acid–Schiff stain. Note the massive thickening of the basement membrane of the ciliary body epithelia, reminiscent of changes in the mesangium of the renal glomerulus

56. (A) A tangle of abnormal vessels lies just beneath the internal limiting membrane of the retina on the right half of the photomicrograph (between arrows).

57. B) In this section stained by periodic acid–Schiff, the internal limiting membrane is indicated by the thick arrows, and the posterior hyaloid of the vitreous is indicated by the thin arrow.

58. (C) Ophthalmoscopic view of retinal neovascularization (known clinically as neovascularization “elsewhere” in contrast to neovascularization of the optic disc) creating a neovascular membrane

59. Retinopathy of Prematurity: Retrolental Fibroplasia Incompletely vascularized temporal (lateral) retinal periphery at term Premature or low-birth-weight infants treated with oxygen: Constriction of immature retinal vessels in the temporal periphery Resulting retinal tissue distal to the zone becomes ischemic Retinal ischemia: Upregulation of proangiogenic factors like VEGF (vascular endothelial growth factor) Triggers retinal angiogenesis (formation of new blood vessels) Contraction of peripheral retinal neovascular membrane: "Drag" on the temporal aspect of the retina Displacement of the macula laterally (temporal to optic nerve) Neovascular membrane contraction: Potential force causing retinal detachment Use of VEGF inhibition under investigation for treatment

60. Sickle Retinopathy, Retinal Vasculitis, Radiation Retinopathy Retinopathy in sickle hemoglobinopathies: Two types: nonproliferative and proliferative Common pathway: vascular occlusion Nonproliferative form (hemoglobin SS and SC genotypes): Vascular occlusions contribute to hemorrhages Visible changes: salmon patches, iridescent spots, black sunburst lesions Pre-retinal hemorrhage organization: Retinal traction (pulling) Risk of retinal detachment Vascular occlusions contribute to angiogenesis: Upregulation of VEGF and basic fibroblast growth factor Florid neovascularization in peripheral retina ("sea-fans") Neovascularization in other clinical settings: Peripheral retinal vasculitis (inflammation of retinal blood vessels) Radiation used in intraocular tumor treatment Common feature: Damage to retinal vessels Zones of retinal ischemia trigger retinal angiogenesis Complications: hemorrhage and traction Possible risk of retinal detachment

61. Retinal Degeneration AMD results from damage to the macula, which is required for central vision. Two forms: dry and wet AMD. Dry AMD: Ophthalmoscopic characteristics: Diffuse or discrete deposits in the Bruch membrane (drusen). Geographic atrophy of the retinal pigment epithelium (RPE). Severe vision loss possible. Oral consumption of zinc and vitamins with antioxidant properties may slow progression. No effective treatment currently available. Regenerative approach using stem cells under investigation.

62. Retinal Degeneration Wet AMD: Characterized by choroidal neovascularization: Vessels originating from the choriocapillaris penetrate the Bruch membrane beneath the RPE. Neovascular membrane may penetrate the RPE and sit beneath the neurosensory retina. Vessels in the membrane may leak, leading to macular scars or hemorrhage. Treatment : Mainstay: Injection of VEGF antagonists into the vitreous. Evaluation of photodynamic therapy effectiveness ongoing. Choroidal neovascular membranes can develop in unrelated conditions such as pathologic myopia, Bruch membrane disruption, or an immune response to systemic histoplasmosis. Pathogenesis involves the RPE, Bruch membrane, and choriocapillaris as a functional unit affecting photoreceptor health. Genes like CFH (complement factor H) and other complement regulatory genes play a role in AMD pathogenesis, with variants associated with decreased function. Environmental exposure, especially cigarette smoking, may increase AMD risk, particularly in genetically predisposed individuals.

63. Retinitis Pigmentosa Inherited condition resulting from mutations affecting rods, cones, or RPE. Can cause varying degrees of visual impairment, including total blindness. Inheritance patterns: X-linked recessive , Autosomal recessive or Autosomal dominant (onset correlates with inheritance pattern) Associated with syndromes: Bardet-Biedl syndrome , Usher syndrome & Refsum disease Can develop in isolation ( nonsyndromic retinitis pigmentosa). Loss of rods and cones to apoptosis, with varying proportions. Clinical features: Retinal atrophy Constriction of retinal vessels Optic nerve head atrophy ("waxy pallor" of optic disc) Accumulation of retinal pigment around blood vessels Early night blindness and constricted visual fields due to rod loss. Central visual acuity affected as cones are lost. Electroretinogram reveals characteristic abnormalities

64. Retinitis Infectious retinitis caused by various pathogens. Candida-related retinitis: Dissemination hematogenously to the retina. Common in intravenous drug abuse or systemic candidemia. Results in multiple retinal abscesses . Cytomegalovirus retinitis: Significant cause of visual morbidity in immunocompromised individuals, especially those with AIDS .

65. Neoplasms: Retinoblastoma: Most common primary intraocular malignancy in children. Cell of origin is a neuronal progenitor, not a primitive retinal cell. In approximately 40% of cases, retinoblastoma occurs in individuals with a germline mutation of one RB allele. Requires a second somatic mutation to lose RB gene function. In sporadic cases, both RB alleles are lost through somatic mutations. Retinoblastomas in individuals with germline mutations are often bilateral and may be associated with pinealoblastoma ("trilateral" retinoblastoma). Morphology: Tumors may contain undifferentiated and differentiated elements. Undifferentiated cells: small, round cells with hyperchromatic nuclei. Well-differentiated tumors: Flexner-Wintersteiner rosettes and fleurettes reflecting photoreceptor differentiation. Degree of tumor differentiation does not correlate with prognosis. Viable tumor cells encircle tumor blood vessels, with necrotic areas in avascular regions. Focal zones of dystrophic calcification are characteristic.

66. Retinoblastoma. Gross photograph of retinoblastoma. Tumor cells appear viable when in proximity to blood vessels, but necrosis is seen as the distance from the vessel increases.

67. Retinoblastoma cont.… Treatment approach: Chemotherapy administration, including selective delivery through the ophthalmic artery, to reduce tumor burden. Laser treatment or cryopexy to obliterate tumors after chemoreduction. Potential spread to the brain and bone marrow, rare dissemination to the lungs. Adverse prognostic factors: Extraocular extension Invasion along the optic nerve Choroidal invasion Variant: Retinocytoma or retinoma, a premalignant lesion. Heritable retinoblastoma may present with retinoblastoma in one eye and retinocytoma in the other eye.

68. Lymphoma Primary retinal lymphoma is an aggressive tumor that involves the neurosensory retina and the RPE. It tends to occur in older individuals and can mimic uveitis clinically. Most cases are diffuse large B-cell lymphomas. Spread to the brain commonly occurs via the optic nerve. Diagnosis relies on demonstrating lymphoma cells in vitreous aspirates.

69. Optic Nerve Sensory tract of the central nervous system. Surrounded by meninges, and cerebrospinal fluid circulates around the nerve. Pathology of the Optic Nerve: The optic nerve's pathology is similar to that of the brain. Common primary neoplasms include: Glioma (typically pilocytic astrocytomas) Meningioma

70. Optic Nerve cont … Anterior Ischemic Optic Neuropathy (AION): A condition similar to stroke in some aspects. A spectrum of optic nerve injuries, ranging from ischemia to infarction. Transient interruptions in blood flow can result in episodes of transient loss of vision. Total interruption of blood flow can lead to optic nerve infarction, which can be segmental or total. Zones of relative ischemia may surround segmental infarcts. Optic nerve function in poorly perfused but not infarcted zones may recover. Infarction of the optic nerve results in permanent visual loss. Causes of Interruption in Blood Supply: Inflammation of the vessels supplying the optic nerve. Embolic or thrombotic events. Temporal Arteritis: Temporal arteritis can cause bilateral total infarcts of the optic nerve. Urgent treatment with high doses of corticosteroids is crucial to manage this condition effectively.

71. Papilledema Edema of the head of the optic nerve. Causes: Compression of the nerve, such as from a primary neoplasm of the optic nerve, leading to unilateral disc edema. Elevated cerebrospinal fluid pressure surrounding the nerve, resulting in bilateral disc edema. Effects on optic nerve: The increased pressure around the optic nerve contributes to venous stasis and interferes with axoplasmic transport. Nerve head swelling occurs as a consequence. Ophthalmoscopic findings: In papilledema, the optic nerve head appears swollen and hyperemic. In the relatively acute phases of anterior ischemic optic neuropathy, the optic nerve head appears swollen and pale due to decreased nerve perfusion. Papilledema secondary to increased intracranial pressure: The optic nerve may remain congested for a prolonged period.

72. In the acute phases of AION the optic nerve may be swollen, but it is relatively pale because of decreased perfusion. In papilledema secondary to increased intracranial pressure, the optic nerve is typically swollen and hyperemic.

73. (C) Normally, the termination of Bruch membrane (arrowheads) is aligned with the beginning of the neurosensory retina, as indicated by the presence of stratified nuclei (arrows), but in papilledema the optic nerve is swollen, and the retina is displaced laterally.

74. Glaucomatous Optic Nerve Damage The majority of individuals with glaucoma have elevated intraocular pressure. Normal-tension glaucoma: A small group of individuals develop visual field and optic nerve changes typical of glaucoma despite having normal intraocular pressure. Neuronal susceptibility to the effects of elevated intraocular pressure: There is a spectrum of susceptibility among individuals. Current research focus: Understanding mechanisms for protecting optic nerve axons from injury. Morphology of Glaucomatous Optic Nerve Damage: Characteristic features: Diffuse loss of ganglion cells and thinning of the retinal nerve fiber layer (Fig. 29.26). Optical coherence tomography can be used to measure the thickness of the retinal nerve fiber layer. In advanced cases: The optic nerve shows both cupping and atrophy, which is a combination unique to glaucoma. Elevated intraocular pressure in infants and children: Can lead to diffuse enlargement of the eye ( buphthalmos ) or enlargement of the cornea ( megalocornea ). Prolonged elevation of intraocular pressure in adulthood: Can result in focal thinning of the sclera. Uveal tissue may line ectatic sclera, forming a staphyloma.

75. (A) Left panel, normal retina; right panel, the retina in long-standing glaucoma (same magnification).

76. (B) Glaucomatous optic nerve cupping results in part from loss of retinal ganglion cells, the axons of which populate the optic nerve.

77. (C) The arrows point to the dura of the optic nerve. Notice the wide subdural space, a result of atrophy of the optic nerve.

78. Optic Neuritis Optic neuritis is characterized by inflammation or demyelination of the optic nerve. Multiple sclerosis-associated optic neuritis: Optic neuritis can be the initial sign of multiple sclerosis (MS) in some cases. Approximately 50% of patients with optic neuritis develop MS within 15 years. Magnetic resonance imaging (MRI) of the brain can detect white matter lesions, which increase the risk of developing MS . Other causes of optic neuritis: Infections (e.g., viral, bacterial, fungal) can lead to optic nerve inflammation. Autoimmune conditions (e.g., neuromyelitis optica , sarcoidosis) may also cause optic neuritis. Clinical presentation: Rapid onset of unilateral vision loss, often accompanied by eye pain exacerbated by eye movement. Visual field defects, such as central scotoma (loss of central vision) or peripheral visual field loss, may be observed. Optic disc swelling (papillitis) may be present on ophthalmoscopic examination. Most cases of optic neuritis are self-limiting, with spontaneous recovery and restoration of vision within a few weeks to months.

79. The End-Stage Eye: Phthisis Bulbi Phthisis bulbi refers to the end-stage of an eye with significant damage. Causes: Trauma Chronic retinal detachment Intraocular inflammation Other conditions Characteristics of Phthisical Eyes: Ciliochoroidal Effusion: Presence of exudate or blood between: Ciliary body and sclera Choroid and sclera Associated with low intraocular pressure (hypotony) Pull of extraocular muscles on hypotonous eye may make it appear square instead of round.

80. The End-Stage Eye: Phthisis Bulbi Cyclitic Membrane: Membrane extending across the eye from one aspect of the ciliary body to the other . Chronic Retinal Detachment: Detachment of the retina from underlying structures. Optic Nerve Atrophy: Atrophy of the optic nerve due to prolonged damage and degeneration. Intraocular Bone: Presence of bone within the eye, originating from osseous metaplasia of the retinal pigment epithelium (RPE). Thickened Sclera: Scleral thickening, especially in the posterior region.

81. End of slide show!