CONJUNCTIVA NON NEOPLASTIC LESIONS

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1 CONJUNCTIVA NON NEOPLASTIC LESIONS Anat Stemmer-Rachamimov, MD Neuropathology Department Massachusetts General Hospital Boston, MA Learning objectives: 1) Review the normal histology and physiology of the conjunctiva 2) Review of common inflammatory disorders 3) Review of some of the non-inflammatory (developmental, degenerations) disorders of the conjunctiva NORMAL ANATOMY AND PHYSIOLOGY The conjunctiva forms a transparent lining of most of the anterior part of the globe and the posterior surface of the eyelids. The conjunctiva merges with the cornea (which is central) at the limbus - a transitional zone where corneal epithelium merges with the conjunctival epithelium and corneal stroma continues into sclera. Conjunctiva derives from the term in Latin and means to bind. The conjunctiva is a continuous mucous membrane with 3 sections: Palpebral: lines the posterior surface of the eyelids, adherent to the tarsal plate. It contains epithelial invaginations (pseudoglands of Henle). Forniceal: lines the fornix; junction between palpebral and bulbar conjunctiva. Loose and redundant (folds) to allow free movement of the globs Bulbar: lines the anterior globe. Associated structures: Caruncle: conjunctival fold in the medial canthus region. The caruncle contains sebaceous glands and hair follicles. Plica semilunare: vertical fold in the medial (nasal) canthal area, lateral to the caruncle. The conjunctiva s main functions is to 1) Allow movement of the eyelids over the cornea without damage 2) Form a barrier to protect the globe from outside injury and infection The epithelium forms a physical barrier to micro organisms (tight junctions). In addition the tear film which contains mucus (secreted by goblet cells in conjunctiva) and secretions from the lacrimal gland provide flow (dilution and movement of foreign particles and organism) as well as local protective agents (secreted IgA, lysozymes).

2 Histology: The outside lining of the conjunctiva is composed of non keratinizing stratified squamous epithelium and underlying substantia propria. The epithelium contains goblet cells (highlighted with PAS). Goblet cells are superficial and their number varies depending on location; most abundant in the fornices and plica semilunaris. There is an abrupt transition of the palpebral epithelium to squamous keratinizing epithelium (skin) of the eyelid at the lid margin and a gradual transition from corneal epithelium to conjunctival epithelium at the limbus. Underlying the loose subepithelial layer is the stroma (substantia propria), a dense connective tissue. Chronic inflammatory cells are normally present in the substantia propria, which may also contain sometimes a follicle with a germinal center. The semilunar fold stroma may contain cartilage. The stroma of the caruncle contains sebaceous glands and striated muscle fibers (orbicularis oculi muscle). The conjunctiva is rich with lymphatics. Development and changes associated with ageing: The conjunctiva develops within the lid folds from ectodermal tissue. Conjunctival epithelium is present already in the 10 th week of gestation. The lid folds fuse in the midline (8 th week) and remain fused until the 20 th week. During ageing the conjunctival stroma becomes thinner and looser. DEVELOPMENTAL DISORDERS: Choriostomas: A mass composed of mature tissue elements in a site where they are not normally present. Congenital. Simple when contain one tissue type, complex when contain more than one. Most are sporadic (not associated with syndromes, not familial). Different types: - Limbal dermoid - Dermolipoma - Epibulbar osseous choristoma - Ectopic lacrimal gland Dermoid: White-yellow, firm, limbal mass present at the infero-temporal quadrant. May have fine hair protruding from its surface. Sometimes extends to involve the cornea. Size varies (2-15 mm). Small dermoids can be asymptomatic, when large may cause astigmatism or encroach on the visual axis. Thought to develop secondary to anomaly in eyelid fold closure with entrapment of skin and mesenchyme. When bilateral or multiple may be hereditary of associated with Goldenhar Syndrome. Histologically composed of epithelium and skin adnexa. Dermolipoma: Common. Often located in the superotemporal quadrant and may extend into the orbit. Clinically may be confused with herniated orbital fat. Histologically composed of epithelium and adipose tissue (skin adnexa not present). Often is small and does not require treatment. When larger, excision for cosmetic reasons is indicated. INFLAMMATORY DISORDERS:

3 Conjunctivitis can be divided using different criteria: - By clinical course- conjunctivitis can be divided into acute and chronic. - By morphology: conjunctivitis associated with membranes and pseudomembranes, cicatricial conjunctivitis, papillary, follicular and granulomatous. - By causative agent: infectious and non infectious (immune mediated). Non-specific symptoms common to all forms of conjunctivitis include conjunctival injection (redness), edema and exudation. In addition, there are other symptoms/signs associated with specific agents (membranes, follicles, periauricular lymphadenopathy, scarring, purulent exudate). Acute conjunctivitis: is characterized by rapid onset and duration less than 4 weeks. Inflammatory response is rich in neutrophils. Inflammatory membranes and pseudo membranes can develop in acute conjunctivitis. These are formed from fibrin and inflammatory cells. True membranes are firmly adherent to the epithelium, and are anchored in granulation tissue, their removal causes bleeding. In contrast, pseudo membranes overlie intact epithelium and can be removed with no associated bleeding. Chronic conjunctivitis: Signs and symptoms develop slowly and duration exceeds 4 weeks. Inflammatory cells are predominantly lymphocytes, plasmacells. Epithelium may show reactive changes, hyperplasia, infolding, formation of epithelial cysts and pseudo cysts (pseudo glands of Henle). Papillary conjunctivitis: clinically the conjunctival surface has a cobblestone pattern. Histologically, there are papillae composed of closely packed lymphoid aggregates around a central vascular core. Plasma cells, eosinophils and mast cells may be also present in varying amounts. Most commonly associated with contact lens use, prosthesis or atopic (allergic) chronic conjunctivitis. Follicular conjunctivitis: Represents follicular hyperplasia. The conjunctival surface shows multiple large, gelatinous masses without central vascular core. Histologically, there are lymphoid aggregates, sometimes with formation of germinal centers. Most commonly associated with viral infections, chlamydia infections (trachoma), psittacosis, infectious mononucleosis. Granulomatous conjunctivitis: The conjunctival granulomas clinically appear as small yellow nodules; histologically are composed from clustered epitheloid macrophages and lymphocytes; with or without necrosis. May be seen in a variety of conditions. Most important are: - sarcoidosis, - foreign body granuloma (synthetic fibers or teddy bear granuloma), - Perinaud oculoglandular syndrome: a granulomatous conjunctivitis associated with periauricular lymphadenopathy. Perinaud oculaoglandular syndrome is associated with several infectious agents, most common is Cat Scratch disease (Bartonella Henselae; Gram negative, seen only with silver stains). Cicatricial conjunctivitis: chronic conjunctivitis associated with extensive scarring. Common examples of cicatricial conjunctivitis are trachoma and ocular cicatricial pemphigoid (see below). -

4 INFECTIOUS CONJUNCTIVITIS Risk factors for infectious conjunctivitis are conditions that compromise the local or systemic defense of the host: immunosuppression, epithelial defects, decreased tear film or blinking (as seen in Parkinsons). Common agents of Infectious conjunctivitis: I. BACTERIA II. VIRUSES III. CHLAMIDIA Bacteria: Bacterial conjunctivitis is the most common form in children (50%) but only constitute a minority of infections in adults (5%). Most common agents are Gram positive bacteria, esp. Hemophilus influenza and Strep pneumonia. Usually self limiting (resolve in 5 days) and caused by direct eye contact with infected secretions. Bacterial conjunctivitis is often bilateral and associated with blepharitis. Characterized by a thick purulent discharge with crusting of the eyes in the morning and in severe cases membrane formation. Bacterial conjunctivitis may be part of a systemic infection: Gonococcal keratoconjunctivitis: Transmission can occur by contact of the eye with infected genital secretions (genital to eye or genital to hand to eye) or via contact of fetus with infected birth canal. May present as hyperacute, severe, purulent conjunctivitis, with membrane formation and ulcerations. Often associated with prominent lymphadenopathy. Virus: Viral conjunctivitis is the most common form in adults. The most common viral agent is adenovirus ( pink eye ) which may occur in epidemics (schools, hospitals). Highly contagious as the virus can survive for 4-10 days on dry surfaces and is transmissible after medical instrumentation is cleaned with alcohol (as opposed to most other viruses). In ophthalmology practice this means there is a risk of transmission through contact tonometry or eyedrops. Multiple adenovirus serotypes (7) are associated with conjunctivitis and there is a broad spectrum of disease. Can be divided into two broad clinical diseases: Epidemic keratoconjunctivitis: Usually unilateral at presentation but may extend to the contralateral eye several days later. Often associated with follicular conjunctivitis and pseudo membrane formation. Bacterial superinfections may occur. In some cases can cause a dramatic hemorrhagic conjunctivitis (differential is from other viruses enteroviruses, coxackie Pharyngoconjunctival fever: Acute onset of fever, pharyngitis, follicular conjunctivitis. Ther is often associated periauricular lymphadenopathy. May cause outbreaks in schools and summer camps. More common in children. Infection occurs from contaminated swimming pool water. Other (less common) viruses which may cause conjunctivitis are molluscum, Herpes Simplex, Herpes Zoster, coxackie and enteroviruses. Chlamydia are small obligate intracellular organisms that can only replicate inside eukaryotic host cells. There are 4 species of Chlamydia: C. trachomatis, C. pneuroniae, C. psittaci, and C. pectorum. Clamydia exist in two morphological forms: the elementary body, an infective extracellular form and the larger, reticular body, an intracellular replicating form. Chlamidia infect epithelial cells of the urogenital system and conjunctiva. In the cell they are inside intracytoplasmic inclusions. Replication within the cell is

5 followed by lysis of the cell, necrosis and inflammation. Chlamydial infections of the eye are caused by different strains of C. Trachomatis and depending on the organism, the age, and immune system cause different forms of ocular or oculogenital infections: trachoma, adult oculogenital disease, neonatal inclusion conjunctivitis, adult inclusion conjunctivitis. Adult oculogenital disease: Caused by the C. Trachoma strains D-K. The most common sexually transmitted disease in developed countries. May be asymptomatic or cause urethritis and prostatitis in men or cervicitis or PID in women. May spread to the conjunctiva by infected water or genital secretions giving rise to Adult inclusion conjunctivitis. Clinically manifests as follicular conjunctivitis in the lower fornix with periauricular lymphadenopathy. It is important to treat the patient and the partner. Neonatal chlamydial conjunctivitis (paratrachoma): Neonates contract the infection through passage in an infected birth canal and clinical manifestations occur 1-2 weeks after birth. There is acute, bilateral infection with swelling of the eyelids and mucopurulent discharge. In contrast to adult forms, there is no follicular response. The neonatal infection may involve other systems (pneumonia, otitis media) and therefor should be treated systemically. Trachoma: is a leading cause of blindness in underdeveloped countries, and is caused by Chlamydia Trachomatis serotypes A-C. It is a chronic, cicatrizing conjunctivitis that causes scarring of the lids and cornea. Infection is spread by direct contact with infected eye secretions, flies and contact with contaminated water. Onset is usually in the first year of life. The acute infection is characterized by superficial keratitis, epithelial hyperplasia and neovascularization. There is follicular conjunctivitis in the upper tarsus and limbus. In the limbus involution of necrotic follicles leaves a row of shallow depression (Herbert pits). The chronic phase is characterized by conjunctival scarring with formation of a linear scar across the upper tarsus (Arlt line). Scarring can result in tear drainage obstruction, destruction of conjunctival goblet cells, trichiasis and endtropion. The dry eye and repeated traumas can cause corneal opacification and conjunctival epidermalization. There is a WHO classification for the stages of progression of Trachoma: from mild follicular conjunctivitis, to intense follicular conjunctivitis, tarsal scarring, trichiasis and corneal opacification. The pathogenesis of the scar tissue in Trachoma is explored in multiple studies. There is little correlation between infection and clinical symptoms, the symptoms are better associated with the hosts inflammatory response, activation of fibrogneic pathways and secondary bacterial pathogens. Laboratory diagnostic procedures include: 1) Microscopic examination of conjunctival smears show epithelial cells, mixed inflammatory cells and macrophages containing debris. Special stained such as Giemsa, periodic acid Schiff which highlight intracytoplasmic inclusions in the neonatal form. 2) Culture: Chlamydia require cell culture (do not grow in media). 3) Detection of chlamydial antigen (immunofluorescence) 4) Confocal microscopy 5) Detection of chlamydial nucleic acids by molecular methods. Funghi: Uncommon cause unless complicating another infection. Rhinosporidium may cause fungal conjunctivitis in India.

6 IMMUNE MEDIATED CONJUNCTIVITIS Immune mediated (non infectious) conjunctivitis include allergic conjunctivitis, contact lens wear conjunctivitis, giant papillary conjunctivitis, atopic and vernal conjunctivitis. Often bilateral and papillary. Patients often have other atopic conditions. The most prominent ocular symptom is itching (3). Symptoms may be aggravated by contact lens wear. Treatment includes topical antihistamines and mast cell stabilizers as well as avoidance of allergens if possible. Another group of immune mediated conjunctivitis are conjunctivitis associated with systemic autoimmune disorders (Steven Johnson, mucous membrane pemphigoid). Allergic conjunctivitis: Associated with common air born allergens (animal dandruff, dust, pollens). The allergen enters the tear film and comes in contact with conjunctival mast cells. IgE mediated Very common (20% of population). May be seasonal (spring and summer) or perennial (all year, less common). Characterized by acute attacks of redness, watering and itching of the eyes. Often associated with nasal discharge and sneezing. Contact lens wear conjunctivitis: Mechanism not fully understood; may be due to hypersensitivity to contact lens polymer, to allergens stuck to lens or repeated mechanical trauma. Chronic, papillary conjunctivitis. Vernal conjunctivitis: Presentation usually occurs in young boys (7-15 years old). More common in Africa. Characterized by formation of giant papillae on the superior tarsus. This is an IgE mediated disorder. The large limbal papillae may cause blurred vision. Characterized by intense itching, lacrimation, blinking and thick mucous discharge (chewing gum consistency), which is rich in eosinophils. Giant papillary conjunctivitis: Associated with long term wear of contact lenses, prosthesis or filtering blebs. Thought to be secondary to cell mediated hypersensitivity reaction to material that accumulates of the foreign body. Ocular cicatricial pemphigoid (OCP): Systemic auto immune disease that primarily affects mucous membranes, with ocular manifestations. Most common in middle age females. Often involves both eyes. The underlying process is an autoimmune reaction to the epithelial basement membrane (type II hypersensitivity response) with formation of IgG or IgA to basement membrane proteoglycans. In OCP the patient presents with persistent conjunctivitis and subepithelial vesicles that burst giving rise to ulcers. As the disease progresses there is distortion of the lids, loss of conjunctival goblet cells and dry eyes, and scarring with restriction of lid and ocular movements. The disease is related to bullous pemphigoid, in which the skin is affected. Histological hallmark of OCP is the formation of subepithelial bullae with mixed chronic inflammatory infiltrates in the conjunctiva. Later changes include granulation tissue, scarring and epidermization of the conjunctiva. Diagnosis: Frozen sections immunofluorescence shows antibody and immune complex deposition in basement membrane. DEGENERATIVE DISORDERS Pterygium and Pinguecula: Subepithelial lesions with elastotic degeneration in the conjunctiva (pinguecula) or extending to cornea (pterygium). The lesions are painless, but may be associated with

7 dryness and foreign body sensation in the eye and when cornea is involved may obstruct vision. On examination it appears like a pinkish triangular wedge of vascular conjunctiva on the surface of the limbus or conjunctiva. The Incidence and prevalence of pterygium and pinguecula vary widely by race and location. There is association with exposure to UV light esp. during the first 10 years of life, and are more common in rural and dusty environment. Pterygium is more common with increasing age and among nonwhite persons, particularly those of African origin. Histological features are conjunctival epithelium, a vascular subepithelium with collagen deposition, edema and elastotic degeneration. The epithelium may be hyperplastic or atrophic and may harbor dysplasia. Pterygium should be clinically and histologically be distinguished from pseudo pterygium which is a conjunctival fold often secondary to corneal disease. Histologically pseudo pterygium will not have elastotic degeneration of the subepithelium connective tissue. SELECTED REFERENCES 1) Gonzalez-Lopez JJ. et al. Adenoviral keratoconjunctivitis: an update. Archivos de la Sociedad Espanola de Oftalmologia, 2013; 88: ) Dart JKG et al. Identification and control of nosocomial adenovirus keratoconjunctivitis in an ophthalmic department. Br J Ophthalmol, 2009;93: ) Hu VH et al. Epidemiology and control of Trachma: systematic review. Trop Med Int Health, 2010:15: ) ThyleforscB et al. A simple system for the assessment of Trachoma and its complications. Bull World Health Organ, 1987; 65: ) Polack S et al. Mapping the global distribution of Trachoma. Bull World Health Organ, 2005; 83: ) Burton MJ et al. What is causing active trachoma? The role of nonchlamydial bacterial pathogens in a low prevalence setting. 2011, Invest Ophthlmol Vis Sci ; 52: ) Hu VH et al. In vivo confocal microscopy in scarring trachoma. 2011, Opthalmology; 18: