Conjunctiva

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7

Conjunctiva

Normal Anatomy

I. The conjunctiva (Fig. 7.1) is a mucous membrane, similar to mucous membranes elsewhere in the body, whose surface is composed of nonkeratinizing squamous epithelium, intermixed with goblet (mucus) cells, Langerhans’ cells (dendritic-appearing cells expressing class II antigen), and occasional dendritic melanocytes.

Stem cells for the epithelium are located near the limbus, and their loss can result in exhaustion of the conjunctival epithelial population. Such stem cell loss may have many causes, including the use of mitomycin C in glaucoma filtration surgery, which may be exhibited as a late complication.

A. Idiopathic stem cell deficiency is rare, most commonly found in women, and may be familial in some cases. Patients exhibit severe photophobia and, on clinical examination, have corneal vascularization accompanied by loss of the limbal palisades of Vogt, hazy peripheral corneal epithelium, and the presence of conjunctival goblet cells by impression cytology.
A conjunctivalized pannus may develop on the cornea of those with total limbal stem cell deficiency. Characterization of this tissue demonstrates that it is not corneal, as evidenced by failure to stain for cornea-specific K12 mRNA and protein, but rather, it is conjunctival, as evidenced by the presence of goblet cells, the weak expression of K3, and the strong expression of K19.

B. The homeostasis of the conjunctiva is dependent, in part, on the maintenance of a normal tear film, which is composed of lipid, aqueous, and mucoid layers (the mucoid layer is most closely apposed to the corneal epithelium and the lipid layer is at the tear film : air interface). Multiple disorders are associated with abnormal tear composition, quantity and/or quality, and secondary ocular surface changes.

1. Tear film abnormalities have been documented in association with cigarette smoking, pseudoexfoliation syndrome, and pseudoexfoliation glaucoma, and they are reflected in abnormal conjunctival impression cytology and altered goblet cell morphology.

Cigarette smoking has a deteriorating effect on the tear film in general and on its lipid layer in particular. It results in decreased quantity and quality of the tear film and decreased corneal sensitivity and squamous metaplasia, and this deterioration is related to the amount of smoking.

2. The pattern of human leukocyte antigen (HLA)-DR expression in mild and moderate dry eyes appears to reflect disease progression, and it suggests that inflammation may be a primary cause of ocular surface damage.

3. Squamous metaplasia of the ocular surface epithelium and ocular tear function abnormalities have been associated with interferon and ribavirin treatment for hepatitis C. Similarly, conjunctiva in β-thalassemia exhibits goblet cell loss and conjunctival squamous metaplasia.

4. Inflammation plays a significant role in the pathogenesis of dry eye.

5. Complete androgen-insensitivity syndrome may promote meibomian gland dysfunction and increase the signs and symptoms of dry eye. In patients with dry eyes, the degree of conjunctival metaplasia, characterized by increased stratification, epithelial cellular size, and a general loss of goblet cells, correlates with the clinical severity of their disorder.

6. Mucin gene expression levels, particularly MUC1, are decreased in dry eye and are biomarkers that can be evaluated using impression cytology specimens.

7. Marx’s line represents a narrow line of epithelial cells posterior to the tarsal gland orifices along the lid marginal zone, averaging 0.10 mm in width, and is stained with lissamine green dye. It is believed to be the natural site of frictional contact between the eyelid margin and the surfaces of the bulbar conjunctiva and cornea, rather than the edge of the tear meniscus or location of the edge of the lacrimal river.

II. The conjunctival epithelium rests on a connective tissue, the substantia propria.

III. The conjunctiva is divided into three zones: tarsal, fornical–orbital, and bulbar.

A. The substantia propria of the tarsal conjunctiva adheres tightly to the underlying tarsal connective tissue, whereas the substantia propria of the bulbar conjunctiva (and even more so the fornical–orbital conjunctival substantia propria) adheres loosely to the underlying tissue (the fornical–orbital conjunctiva being thrown into folds).

The bulbar conjunctiva inserts anterior to Tenon’s capsule toward the limbus. Small ectopic lacrimal glands of Krause are found in both upper and lower fornices, with very few on the nasal side; glands of Wolfring are found around the upper border of the tarsus in the nasal half of the upper lid and, in lesser numbers, in the lower lid near the lower tarsal border; and glands of Popoff reside in the plica semilunaris and caruncle.

B. The periodic acid–Schiff (PAS) stain-positive goblet cells are most numerous in the fornices, the semilunar fold, and the caruncle. The latter is composed of modified conjunctiva containing hairs, sebaceous glands, acini of lacrimal glandlike cells, globules of fat, occasionally smooth-muscle fibers, and rarely cartilage.

C. The tarsal conjunctiva meets the keratinized squamous epithelium of the skin on the intermarginal surface of the lid near its posterior border.

Congenital Anomalies

Cryptophthalmos (Ablepharon)

See Chapter 6.

Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease)

I. It is a generalized vascular dysplasia characterized by multiple telangiectases in the skin, mucous membranes, and viscera, with recurrent bleeding and an autosomal-dominant inheritance pattern.

No evidence of abnormalities in platelet aggregation or of qualitative abnormalities of factor VIII complex is found. Conjunctival hemorrhagic telangiectasia can give rise to “bloody tears.” Occasionally, telangiectases are observed in the retina and may mimic hypertensive or diabetic retinopathy.

II. Dilated conjunctival blood vessels, frequently in a star or sunflower shape, may appear at birth but are not usually fully developed until late adolescence or early adult life.

III. Histologically, abnormal, dilated blood vessels are seen in the conjunctival substantia propria.

Ataxia–Telangiectasia (Louis–Bar Syndrome)

See Chapter 2.

Dermoids, Epidermoids, and Dermolipomas

See later in this chapter and Chapter 14.

Vascular Disorders

Sickle-Cell Anemia

See Chapter 11.

I. In homozygous sickle-cell disease, conjunctival capillaries may show widespread sludging of blood. The venules may show saccular dilatations.

II. The characteristic findings (marked in SS disease and mild in SC disease), however, are multiple, short, comma-shaped or curlicued conjunctival capillary segments, mostly near the limbus, often seemingly isolated from the vascular network (Paton’s sign).

Similar conjunctival capillary abnormalities may occasionally be seen in patients without SC disease. Inferior conjunctival abnormalities, however, are found almost exclusively in patients with SC disease. The vascular abnormalities seem positively related to the presence of sickled erythrocytes. The comma-shaped capillaries are most easily seen after local application of phenylephrine.

III. Histologically, the capillary lumen is irregular and filled with sickled erythrocytes.

Ataxia–Telangiectasia

See Chapter 2.

Diabetes Mellitus

See section Conjunctiva and Cornea in Chapter 15.

Inflammation

Basic Histologic Changes

I. Acute conjunctivitis (Fig. 7.3)

A. Edema (chemosis), hyperemia, and cellular exudates are characteristic of acute conjunctivitis.

B. Inflammatory membranes (Fig. 7.4)

1. A true membrane consists of an exudate of fibrin–cellular debris firmly attached to the underlying epithelium by fibrin that characteristically, on attempted removal, the epithelium is stripped off and leaves a raw, bleeding surface.

The condition may be seen in epidemic keratoconjunctivitis, Stevens–Johnson syndrome, and infections caused by Pneumococcus, Staphylococcus aureus, Streptococcus pyogenes, and Corynebacterium diphtheriae.

2. A pseudomembrane consists of a loose fibrin–cellular debris exudate not adherent to the underlying epithelium, from which it is easily stripped, usually without bleeding.

3. Ligneous conjunctivitis (Fig. 7.5) is an unusual bilateral, chronic, recurrent, membranous or pseudomembranous conjunctivitis of childhood, most commonly in girls, of unknown cause. The condition persists for months to years and may become massive.

a. The conjunctivitis is characterized by woodlike induration of the palpebral conjunctiva, chronicity, and rapid recurrence after medical or surgical treatment. Severe corneal complications may occur.

b. Similar lesions may also occur in the larynx, vocal cords, trachea, nose, vagina, cervix, and gingiva. Rarely, the middle ear may exhibit a similar histopathologic process.

c. Severe type I plasminogen deficiency has been linked to ligneous conjunctivitis.

d. Histologically, the conjunctival epithelium is thickened and may be dyskeratotic. The subepithelial tissue consists of an enormously thick membrane composed primarily of fibrin, albumin, immunoglobulin G (IgG), and an amorphous eosinophilic material containing a sprinkling of T and B lymphocytes and plasma cells.

C. Ulceration, or loss of epithelium with or without loss of subepithelial tissue associated with an inflammatory cellular infiltrate, may occur with acute conjunctivitis.

D. A phlyctenule usually starts as a localized, acute inflammatory reaction, followed by central necrosis and infiltration by lymphocytes and plasma cells.

II. Chronic conjunctivitis (Fig. 7.6)

A. The epithelium and its goblet cells increase in number (i.e., become hyperplastic).

Infoldings of the proliferated epithelium and goblet cells may resemble glandular structures in tissue section and are called pseudoglands (Henle). Commonly, the surface openings of the pseudoglands, especially in the inferior palpebral conjunctiva, may become clogged by debris. They form clear or yellow cysts called pseudoretention cysts, containing mucinous secretions admixed with degenerative products of the epithelial cells.

B. The conjunctiva may undergo papillary hypertrophy (Fig. 7.7), which is caused by the conjunctiva being thrown into folds. Papillary hypertrophy is primarily a vascular response.

1. The folds or projections are covered by hyperplastic epithelium and contain a core of vessels surrounded by edematous subepithelial tissue infiltrated with chronic inflammatory cells (lymphocytes and plasma cells predominate).

2. The lymphocyte (even lymphoid follicles) and plasma cell infiltrations are secondary.

Clinically, the small (0.1–0.2 mm), hyperemic projections are fairly regular, are most marked in the upper palpebral conjunctiva, and contain a central tuft of vessels. The valleys between the projections are pale and relatively vessel-free. Papillae characterize the subacute stage of many inflammations (e.g., vernal catarrh and the floppy-eyelid syndrome; decreased tarsal elastin may contribute to the laxity of the tarsus in the floppy-eyelid syndrome).

C. The conjunctiva may undergo follicle formation. Follicular hypertrophy (Fig. 7.8) consists of lymphoid hyperplasia and secondary visualization.

Lymphoid tissue is not present in the conjunctiva at birth but normally develops within the first few months. In inclusion blennorrhea of the newborn, therefore, a papillary reaction develops, whereas the same infection in adults may cause a follicular reaction. Lymphoid hyperplasia develops in such diverse conditions as drug toxicities (e.g., atropine, pilocarpine, and eserine), allergic conditions, and infections (e.g., trachoma). It has been reported, presumably, as secondary to extremely thin sclera in high myopia. Clinically, lymphoid follicles are smaller and paler than papillae and lack the central vascular tuft.

D. Vitamin A deficiency or drying of the conjunctiva (e.g., chronic exposure with lid ectropion) may cause keratinization.

E. Chronic inflammation during healing may cause an overexuberant amount of granulation tissue to be formed (i.e., granuloma pyogenicum; see Fig. 6.11).

F. The conjunctiva may be the site of granulomatous inflammation (e.g., sarcoid; see Chapter 4).

G. Conjunctival epithelium of patients on chronic topical medical treatment, such as individuals with glaucoma, demonstrates increased expression of immunoinflammatory markers such as HLA-DR, and interleukins IL-6, IL-8, and IL-10 in impression cytology specimens.

H. Clinical and/or histopathologic demonstration of tarsal conjunctival disease may be evidenced by (1) conjunctival hyperemia and granuloma formation, areas of necrosis, or active fibrovascular changes in the tarsus or conjunctiva; or (2) an inactive fibrovascular scar associated with subglottic stenosis and nasolacrimal duct obstruction in patients with Wegener’s granulomatosis (WG).

III. Ligneous conjunctivitis (see earlier, this chapter).

IV. Scarring of conjunctiva

A. Ocular cicatricial pemphigoid (benign mucous membrane pemphigoid, pemphigus conjunctivae, chronic cicatrizing conjunctivitis, essential shrinkage of conjunctiva)

1. This is a rare, T-cell immune-mediated, bilateral (one eye may be involved first), blistering, chronic conjunctival disease. It may involve the conjunctiva alone or, more commonly, other mucous membranes and skin in elderly people.

The conjunctiva is the only site of involvement in most cases. Drugs such as echothiophate iodide, pilocarpine, idoxuridine, and epinephrine may induce a pseudopemphigoid conjunctival reaction.

2. The disease results in shrinkage of the conjunctiva (secondary to scarring), trichiasis, xerosis, and, finally, reduced vision from secondary corneal scarring.

An acute or subacute papillary conjunctivitis and diffuse hyperemia are common at its onset. One or two small conjunctival ulcers covered by a gray membrane are often noted. Keratinization of the caruncular region (i.e., medial canthal keratinization) is a reliable early sign of ocular cicatricial pemphigoid, especially if entities such as Stevens–Johnson are excluded. The ulcers heal by cicatrization, as new ulcers form. The condition occurs more frequently in women.

3. Approximately 22% of patients who have systemic, nonocular, mucous membrane pemphigoid develop ocular disease.

4. Histology

a. Subepithelial conjunctival bullae rupture and are replaced by fibrovascular tissue containing lymphocytes (especially T cells), dendritic (Langerhans’) cells, and plasma cells.

1) The epithelium has an immunoreactive deposition (immunoglobulin or complement) along its basement membrane zone. The presence of circulating antibodies to the epithelial basement membrane zone can also be helpful in making the diagnosis. Such immunohistochemical confirmation is important because the clinical characteristics of ocular mucous membrane pemphigoid and pseudopemphigoid are similar, which may lead to a clinical misdiagnosis.
Increased expression of connective tissue growth factor has been demonstrated in the conjunctiva of patients with ocular cicatricial pemphigoid, and it is probably one of the factors involved in the pathogenesis of the typical conjunctival fibrosis in the disorder. Macrophage colony-stimulating factor has increased expression in conjunctiva in ocular cicatricial pemphigoid, and there is a positive correlation between its expression and the accumulation of macrophages in conjunctival biopsies in patients with pemphigoid.

2) The vascular and inflammatory components lessen with chronicity, resulting in contracture of the fibrous tissue with subsequent shrinkage, scarring, symblepharon, ankyloblepharon, and so forth. The use of the immunoperoxidase technique in biopsy material may increase the diagnostic yield in clinically suspected cases.

Ocular cicatricial pemphigoid, bullous pemphigoid, and benign mucous membrane pemphigoid, all immune-mediated blistering diseases, resemble each other clinically, histopathologically, and immunologically. Ocular cicatricial pemphigoid, however, appears to be a unique entity separated from the others by antigenic specificity of autoantibodies. Another systemic blistering condition, epidermolysis bullosa acquisita, can cause symblepharon and small, subepithelial corneal vesicles.

3) Expression of macrophage migration inhibitory factor is increased in cicatricial pemphigoid and may help regulate the inflammatory events in this disorder.

4) Elevated numbers of conjunctival mast cells are present in ocular cicatricial pemphigoid, as well as in atopic keratoconjunctivitis and Stevens–Johnson syndrome.

Pemphigus, a group of diseases that have circulating antibodies against intercellular substances or keratinocyte surface antigens. Unlike pemphigoid, it is characterized histologically by acantholysis, resulting in intraepidermal vesicles and bullae rather than subepithelial vesicles and bullae. The bullae of pemphigus, unlike those of pemphigoid, tend to heal without scarring. In pemphigus, the conjunctiva is rarely involved, and even then scarring is not a prominent feature. Unilateral refractory (erosive) conjunctivitis may be an unusual manifestation of pemphigus vulgaris.

5) The histopathologic alterations in the ocular surface from abnormal tear film vary considerably depending on the nature of the precipitating ocular condition.

a) Dryness secondary to facial nerve palsy is an aqueous-deficient process resulting in a relatively pure squamous metaplasia response.

b) Ocular cicatricial pemphigoid is primarily a mucous-deficient syndrome and results in hypertrophy and hyperplasia of the ocular surface epithelium.

c) Patients with primary Sjögren syndrome, which involves deficiency of both the aqueous and mucin tear components, start with a squamous metaplasia process but display hypertrophy and hyperplasia at later stages of the disease.

B. Secondary scarring occurs in many conditions. Examples include chemical burns, erythema multiforme (Stevens–Johnson syndrome), old membranous conjunctivitis (diphtheria, β-hemolytic Streptococcus, adenovirus, and primary herpes simplex), trachoma, trauma (surgical or nonsurgical), paraneoplastic pemphigus, and pemphigus, vulgaris and deliberate chronic use of high-dose topical hydrogen peroxide Cicatricial conjunctivitis may be a manifestation of porphyria cutanea tarda.

C. Conjunctival involvement in toxic epidermal necrolysis has been reported in association with autoimmune polyglandular syndrome type I, which is defined as the presence of two of the following diseases: Addison’s disease, hypoparathyroidism, and chronic mucocutaneous candidiasis.

D. Ocular complications of autoimmune polyendocrinopathy syndrome type I are characterized by reduced tear production (63%) that can result in corneal scarring and vision loss. Other ocular complications include lens opacities (18%), hypotrichosis (12%), anisometropic amblyopia (5.9%), and myopia (5.9%).

Specific Inflammations

Infectious

I. Virus—see subsection Chronic Nongranulomatous Inflammation in Chapter 1.

A. As an alternative to viral culture, the most sensitive and specific methods of confirming adenovirus conjunctival infection are PCR (100%), IgM detection (92.9%), and direct antigen detection by fluorescent stain (85.8%).

II. Bacteria—see sections Phases of Inflammation in Chapter 1 and Suppurative Endophthalmitis and Panophthalmitis in Chapter 3. Also see Chlamydiae below.

III. Chlamydiae cause trachoma, lymphogranuloma venereum, and ornithosis (psittacosis).

A. They are gram-negative, basophilic, coccoid, or spheroid bacteria.

B. The chlamydiae are identified taxonomically into order Chlamydiales, family Chlamydiaceae, genus Chlamydia, and species trachomatis and psittaci.

The agents that cause both trachoma and inclusion conjunctivitis, Chlamydia trachomatis, are almost indistinguishable from each other, and the term TRIC agent encompasses both. Reproduction of chlamydiae starts with the attachment and penetration of the elementary body, an infectious small particle 200–350 nm in diameter with an electron-dense nucleoid, into the host cell cytoplasm. The phagocytosed agent surrounded by the invaginated host cell membrane forms a cytoplasmic inclusion body. The elementary body then enlarges to approximately 700–1000 nm in diameter to form a nonmotile obligate intracellular (cytoplasmic) parasite known as an initial body that does not contain electron-dense material. Initial bodies then divide by binary fission into numerous, small, highly infectious elementary bodies. The host cell ruptures, the elementary bodies are released, and a new infectious cycle begins.

C. Trachoma (Fig. 7.9)

1. Trachoma, caused by the bacterial agent C. trachomatis, is one of the world’s leading causes of blindness and primarily affects the conjunctival and corneal epithelium. Healing is marked by scarring or cicatrization.

2. In vivo confocal microscopy can be used clinically to quantify inflammatory and scarring changes in the conjunctiva in trachoma in which dendritic cells are closely associated with the scarring process.

3. Histology of MacCallan’s four stages:

a. Stage I: Early formation of conjunctival follicles, subepithelial conjunctival infiltrates, diffuse punctate keratitis, and early pannus

1) The conjunctival epithelium undergoes a marked hyperplasia, and its cytoplasm contains clearly defined, glycogen-containing intracellular microcolonies of minute elementary bodies and large basophilic initial bodies (epithelial cytoplasmic inclusion bodies of Halberstaedter and Prowazek). The subepithelial tissue is edematous and infiltrated by round inflammatory cells.

2) Fibrovascular tissue from the substantia propria proliferates and starts to grow into the cornea under the epithelium, destroying Bowman’s membrane; the tissue is then called an inflammatory pannus.

b. Stage II: Florid inflammation, mainly of the upper tarsal conjunctiva with the early formation of follicles appearing like sago grains, and then like papillae. The follicles cannot be differentiated histologically from lymphoid follicles secondary to other causes (e.g., allergic).

1) The corneal pannus increases, and large macrophages with phagocytosed debris (Leber cells) appear in the conjunctival substantia propria.

c. Stage III: Scarring (cicatrization): in the peripheral cornea, follicles disappear, and the area is filled with thickened, transparent epithelium (Herbert’s pits); as the palpebral conjunctiva heals, a white linear horizontal line or scar forms near the upper border of the tarsus (von Arlt’s line). Cicatricial entropion and trichiasis may result.

Ocular rosacea can produce chronic cicatrizing conjunctivitis of the upper eyelids, which was previously thought to be unique to trachoma. Conjunctival impression cytology in ocular rosacea demonstrates significant ocular surface epithelial degeneration involving both the upper bulbar and inferonasal interpalpebral bulbar epithelium compared to normal individuals. The inflammatory infiltrate of the tarsal conjunctiva is predominantly composed of T cells (CD4+ and CD8+), and this suggests that T cells may be involved in the genesis of both tarsal thickening and conjunctival scarring in the late stages of trachoma.

d. Stage IV: Arrest of the disease

D. Inclusion conjunctivitis (inclusion blennorrhea)

1. Inclusion conjunctivitis is caused by the bacterial agent C. trachomatis (oculogenitale).

2. It is an acute contagious disease of newborns quite similar clinically and histologically to trachoma, except the latter has a predilection for the upper rather than the lower palpebral conjunctiva and fornix.

Inclusion conjunctivitis can also occur in adults, commonly showing corneal involvement (mainly superficial epithelial keratitis but also subepithelial nummular keratitis, marginal keratitis, and superior limbal swelling and pannus formation).

3. Histologically, a follicular reaction is present with epithelial cytoplasmic inclusion bodies indistinguishable from those of trachoma.

E. Lymphogranuloma venereum (inguinale)

1. Lymphogranuloma venereum, caused by C. trachomatis, is characterized by a follicular conjunctivitis or a nonulcerating conjunctival granuloma, usually near the limbus and associated with a nonsuppurative regional lymphadenopathy. The clinical picture is that of Parinaud’s oculoglandular syndrome (see later).

Keratitis may occur, usually with infiltrates in the upper corneal periphery, associated with stromal vascularization and thickened corneal nerves. An associated anterior uveitis may also occur.

2. Histologically, a granulomatous conjunctivitis and lymphadenitis occur, the latter containing stellate abscesses. Elementary bodies and inclusion bodies cannot be identified in histologic sections.

IV. Fungal—see the subsection Fungal, section Nontraumatic Infections in Chapter 4.

V. Parasitic—see the subsection Parasitic, section Nontraumatic Infections in Chapter 4 and see Chapter 8.

VI. Rickettsial—organisms range in size from 250 nm to more than 1 µm, have no cell wall but are surrounded by a cell membrane, and are intracellular parasites.

VII. Parinaud’s oculoglandular syndrome (granulomatous conjunctivitis and ipsilateral enlargement of the preauricular lymph nodes) consists of a granulomatous inflammation and may be caused most commonly by cat-scratch disease but also by Epstein–Barr virus infection, tuberculosis, sarcoidosis, syphilis, tularemia, Leptothrix infection, soft chancre (chancroid—Haemophilus ducreyi), glanders, lymphogranuloma venereum, Crohn’s disease, and fungi.

Noninfectious

I. Physical—see subsections Burns and Radiation Injuries (Electromagnetic) in Chapter 5.

II. Chemical—see subsection Chemical Injuries in Chapter 5.

III. Allergic

A. Allergic conjunctivitis is usually associated with a type 1 hypersensitivity reaction and can be subdivided into acute disorders (seasonal allergic conjunctivitis and perennial allergic conjunctivitis) and chronic diseases (vernal conjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis).
Mast cells play a central role in the pathogenesis of ocular allergy. Their numbers are increased in all forms of allergic conjunctivitis, and they may participate in the process through their activation, resulting in the release of preformed and newly formed mediators. Chronic conjunctivitis may be accompanied by remodeling of the ocular surface tissues.

B. Vernal keratoconjunctivitis (vernal catarrh, spring catarrh; Fig. 7.10)

1. Vernal keratoconjunctivitis is a bilateral, recurrent, self-limited conjunctival disease occurring mainly in warm weather and affecting young people (mainly boys).

a. It is of unknown cause, but it is presumed to be an immediate hypersensitivity reaction to exogenous antigens.

b. The disease is associated with increased serum levels of total IgE, eosinophil-derived products, and nerve growth factor.

c. The cells infiltrating the conjunctiva in vernal conjunctivitis include lymphocytes, eosinophils, mast cells, and natural killer (NK) cells.

Nerve growth factor may play a role in vernal keratoconjunctivitis by modulating conjunctival mast cell proliferation, differentiation, and activation. Also, the enzymatic degradation of histamine in both tears and plasma appears to be significantly decreased in patients who have vernal keratoconjunctivitis. It has been postulated that vernal conjunctivitis is a Th2 lymphocyte-mediated disease in which mast cells, eosinophils, and their mediators play major roles in the clinical manifestations. This process, therefore, involves the Th2-derived cytokines, IL-4, IL-5, and IL-13, as well as other chemokines, growth factors, and enzymes, which are overexpressed in the disorder. Eventually, structural cells, such as epithelial cells and fibroblasts, are involved both in the inflammatory process and in tissue remodeling, eventuating in the characteristic giant papillae.

A condition called giant papillary conjunctivitis resembles vernal conjunctivitis. It occurs in contact lens wearers as a syndrome consisting of excess mucus and itching, diminished or destroyed contact lens tolerance, and giant papillae in the upper tarsal conjunctiva.

2. Vernal conjunctivitis may be associated with, or accompanied by, keratoconus (or, more rarely, pellucid marginal corneal degeneration, keratoglobus, or superior corneal thinning).

3. Involvement may be limited to the tarsal conjunctiva (palpebral form), the bulbar conjunctiva (limbal form), or the cornea (vernal superficial punctate keratitis form), or combinations of all three. It is mediated, at least in part, by IgE antibodies produced in the conjunctiva.

4. Histology

a. The tarsal conjunctiva may undergo hyperplasia of its epithelium and proliferation of fibrovascular connective tissue along with an infiltration of round inflammatory cells, especially eosinophils and basophils. Papillae that form as a result can become quite large, clinically resembling cobblestones.

b. The epithelium and subepithelial fibrovascular connective tissue of the limbal conjunctival region may undergo hyperplasia and round-cell inflammatory infiltration, with production of limbal nodules.

c. In the larger yellow or gray vascularized nodules, concretions, containing eosinophils, appear clinically as white spots (Horner–Trantas spots).

d. Degeneration and death of corneal epithelium result in punctate epithelial erosions that are especially prone to occur in the upper part of the cornea.

Eosinophilic granule major basic protein (the core of the eosinophilic granule) may play a role in the development of corneal ulcers associated with vernal keratoconjunctivitis.

C. Inflammatory cells (eosinophils and neutrophils) in brush cytology specimens from the tarsus correlate with corneal damage in atopic keratoconjunctivitis. In atopic blepharoconjunctivitis, the tear content of group IIA phospholipase A2 is decreased without any dependence on the quantity of different conjunctival cells.

Other characteristic ocular surface pathologic changes in atopic keratoconjunctivitis include inflammation, decreased corneal sensitivity, tear film instability, and changes in conjunctival epithelial mucins 1, 2, and 4 mRNA expression.

Mast cell densities are increased in the bulbar and tarsal substantia propria in seasonal atopic keratoconjunctivitis and atopic blepharoconjunctivitis, but only in the bulbar substantia propria in atopic conjunctivitis. Ocular surface inflammation, tear film instability, and decreased conjunctival MUC5AC mRNA expression are thought to be important in the pathogenesis of noninfectious corneal shield ulcers in atopic ocular disease. Reactive oxygen species generated by NAD(P)H oxidases in pollen grains may intensify immediate allergic reactions and recruitment of inflammatory cells in the conjunctiva.

D. Hay fever conjunctivitis

E. Contact blepharoconjunctivitis

F. Phlyctenular keratoconjunctivitis

IV. Immunologic

A. Graft-versus-host disease (GvHD) conjunctivitis

1. A significant percentage (perhaps 10%) of patients who have had an allogeneic (an HLA-identical donor, e.g., a sibling) bone marrow transplantation develop a distinct type of conjunctivitis, representing GvHD of the conjunctiva.

2. It presents with pseudomembrane formation secondary to loss of the conjunctival epithelium.

3. In approximately 20% of these cases, the corneal epithelium also sloughs.

Conjunctival ICAM-1 expression is increased in GvHD patients, and the severity of the disease is associated with abnormal tear parameters, goblet cell decrease, and inflammatory markers such as ICAM-1. After autologous bone marrow transplant, there appears to be a subclinical cell-mediated immune reaction; moreover, T cells and macrophages are major contributors to the conjunctivitis of chronic GvHD. Another ocular manifestation mediated by GvHD is keratoconjunctivitis sicca.

B. Wegener’s granulomatosis (WG) should be considered when conjunctival inflammation is recurrent and not typical of other conjunctival inflammatory conditions. Based on assessment of the presence of major basic protein and eosinophil cationic protein, it has been suggested that activated eosinophils in the sclera or conjunctiva of patients with ocular limited WG may predict the progression to complete WG.

C. Inflammatory pseudotumor, characterized by the presence of aggregates of chronic inflammatory cells (lymphocytes, plasma cells, neutrophils, and fibroblasts) without noncaseating epithelioid granuloma formation, has been reported to occur simultaneously in the conjunctiva and lung.

D. Rarely, conjunctival ulceration may be a manifestation of Behçet’s disease, and it is characterized on histopathologic examination by disrupted epithelium, infiltration by both acute and chronic inflammatory cells, and high endothelial venules. Immunohistologic studies of the inflammatory infiltrate reveal primarily T-cell populations admixed with several B cells and CD68+ histiocytes.

V. Neoplastic processes (e.g., sebaceous gland carcinoma) can cause a chronic nongranulomatous blepharoconjunctivitis with cancerous invasion of the epithelium and subepithelial tissues.

A. Sebaceous carcinoma may involve the conjunctival epithelium in 47% of cases, of which the superior tarsal and forniceal conjunctiva are involved in 100%; inferior tarsal conjunctiva, 68%; inferior forniceal conjunctiva, 64%; superior bulbar conjunctiva, 68%; and inferior bulbar conjunctiva, 57%. The caruncle is involved in 54% and the cornea in 39%. Metastasis occurs in 11%.

B. Impression cytology may be useful in the detection of conjunctival intraepithelial invasion by sebaceous gland carcinoma; however, full-thickness biopsies are necessary to confirm the diagnosis.

Injuries

See Chapter 5.

Conjunctival Manifestations of Systemic Disease

Deposition of Metabolic Products

I. Cystinosis (Lignac’s disease)—see Fig. 8.50.

II. Ochronosis—see Chapter 8.

III. Hypercalcemia—see Chapter 8.

IV. Addison’s disease: Melanin is deposited in the basal layer of the epithelium.

V. Mucopolysaccharidoses—see Chapter 8.

VI. Lipidosis—see Chapter 11.

VII. Dysproteinemias

VIII. Porphyria

IX. Jaundice

A. Bilirubin salts are deposited diffusely in the conjunctiva and episclera but not usually in the sclera unless the jaundice is chronic and excessive; even in the latter case, the bulk of the bilirubin is in the conjunctiva (scleral icterus, therefore, is a misnomer).

B. Rarely, the icterus can extend into the cornea.

X. Malignant atrophic papulosis (Degos’ syndrome)—see Chapter 6.

XI. Fabry disease: The characteristic anterior-segment finding is corneal verticillata, which is secondary to glycosphingolipid deposition in the cornea. In vivo confocal microscopy of the conjunctiva demonstrates abnormalities throughout the ocular surface, including bright roundish intracellular inclusions, which are more pronounced in tarsal than in bulbar conjunctiva.

XII. Marfan syndrome with ectopia lentis: Consistent, qualitative abnormalities in conjunctival fibrillin-1 staining pattern can be seen in the conjunctiva.

XIII. Chronic renal failure requiring hemodialysis: Squamous metaplasia of the conjunctival epithelium and corneoconjunctival calcification may be seen.

Abnormal tear function is associated with squamous metaplasia but not with corneoconjunctival calcification. Similarly, although impression cytology demonstrates more frequent and extensive deposits of calcium in the conjunctiva of chronic renal failure patients on regular hemodialysis compared to control patients, the severity of conjunctival squamous metaplasia associated with chronic renal failure appears not to be related to calcium deposition but, rather, to acute conjunctival inflammation.

Deposition of Drug Derivatives

I. Argyrosis (Fig. 7.11)

A. Long-term use of silver-containing medications may result in a slate-gray discoloration of the mucous membranes, including the conjunctiva, and of the skin, including the lids. The discoloration may also involve the nasolacrimal apparatus.

B. Histologically, silver is deposited in reticulin (i.e., loose collagenous) fibrils of subepithelial tissue and in basement membranes of epithelium, endothelium (e.g., Descemet’s membrane), and blood vessels.

II. Chlorpromazine—see Chapter 8.

III. Atabrine

IV. Epinephrine—historically, epinephrine was used to treat glaucoma.

With long-term treatment, conjunctival or corneal deposition has been reported. Epinephrine may deposit under an epithelial bleb, where it becomes oxidized to a compound similar to melanin; in fact, occasionally, the black corneal deposit (black cornea) has been mistaken for malignant melanoma of the cornea. Histologically, an amorphous pink material that bleaches and reduces silver salts is found between corneal epithelium and Bowman’s membrane or in conjunctival cysts.

V. Mercury

VI. Arsenicals

VII. Minocycline hydrochloride, which is a semisynthetic derivative of tetracycline, may cause pigmentation of the sclera and conjunctiva and other tissues, including skin, thyroid, nails, teeth, oral cavity, and bone.

Vitamin A Deficiency: Bitot’s Spot

See Chapter 8.

Sjögren’s Syndrome

See Chapters 8 and 14.

Degenerations

Xerosis

Pterygium

See Chapter 8.

Pinguecula

I. Pinguecula (Fig. 7.13) is a localized, elevated, yellowish-white area near the limbus, usually found nasally and bilaterally, and seen predominantly in middle and late life.

Pigmented, triangular, brown pingueculae may appear during the second decade of Gaucher’s disease. Lesions sampled for biopsy contain Gaucher cells. Patients with Gaucher’s disease may also show congenital oculomotor apraxia (50%) and white retinal infiltrates (38%). Corneal opacities in the posterior two-thirds of the stroma may also occur in Gaucher’s disease. The genetic defect in Gaucher’s disease resides on chromosome 1q21.

II. Histologically, it appears identical to a pterygium except for lack of vascularization and corneal involvement.

A. The subepithelial tissue shows senile elastosis (basophilic degeneration) and irregular, dense subepithelial concretions. The elastotic material stains positively for elastin but is not sensitive to elastase (elastotic degeneration).

B. The elastotic material is positive for elastin, microfibrillar protein, and amyloid P—components that never normally co-localize.

The control of elastogenesis is seriously defective so that the elastic fibers are not immature but are abnormal in their biochemical organization. A marked reduction of elastic microfibrils, rather than an overproduction, appears to prevent normal assembly of elastic fibers. p53 mutations in limbal epithelial cells, probably caused by ultraviolet irradiation, may be an early event in the development of pingueculae, pterygia, and some limbal tumors. The subepithelial dense concretions stain positively for lysozyme.

Amyloidosis

I. Primary

Primary conjunctival amyloidosis should be considered in any patient with recurrent hyposphagma (conjunctival hemorrhage) of unknown cause.

A. Systemic (primary familial amyloidosis; see Fig. 12.10 and also Chapters 8 and 12)

1. Primary amyloidosis, now designated AL amyloidosis (AL amyloid is the same type of amyloid found in myeloma-associated amyloid), is regarded as part of the spectrum of plasma cell dyscrasias with an associated derangement in the synthesis of immunoglobulin.

a. Portions of immunoglobulin light chains, most often fragments of the variable region of the N-terminal end of the λ light chain, are the major constituents of the amyloid filamentous substance (i.e., the deposited amyloid filaments found in tissues are portions of immunoglobulin light chains). λ light chains contain six variable-region subgroups.

Survival in patients who have AL amyloidosis is shortened; congestive heart failure and hepatomegaly are poor prognostic signs.

2. Vitreous opacities are the most important ocular finding, but ecchymosis of lids, proptosis, ocular palsies, internal ophthalmoplegia, neuroparalytic keratitis, and glaucoma may result from amyloid deposition in tissues (see Chapter 12).

3. Amyloid deposition is found around and in walls of ocular blood vessels, especially retinal and uveal. Skin and conjunctiva may be involved, but this is not as important as involvement of other ocular structures.

Rarely, amyloidosis of the lid can be so severe as to cause ptosis. Numerous variants of primary systemic amyloidosis have been described. Some have peripheral neuropathy, which may or may not be associated with vitreous opacities.

B. Familial amyloidotic polyneuropathy (see Chapter 12)

C. Localized (localized nodular amyloidosis; see also Chapter 8)

1. Small and large, brownish-red nodules may be found in the conjunctiva and lids.

2. The intraocular structures are not involved.

3. Based on autopsy analysis, the most frequently involved ocular tissues are as follows: conjunctiva, 89%; iris, 44%; trabecular meshwork, 11%; and vitreous body, 11%.

Lattice corneal dystrophy, one of the inherited corneal dystrophies, is considered by some to be a primary, localized form of amyloidosis of the cornea (see Chapter 8). Rarely, a localized amyloidosis of the cornea unrelated to lattice corneal dystrophy may occur idiopathically (e.g., in climatic droplet keratopathy). Conversely, lattice corneal dystrophy occurs rarely in primary systemic amyloidosis.

II. Secondary

A. Systemic (secondary amyloidosis)—the condition is not as common as primary local amyloidosis.

1. Unlike primary amyloidosis, the amyloid filaments in secondary amyloidosis, termed AA amyloidosis, are related to a nonimmunoglobulin serum protein.

2. Systemic secondary amyloidosis may result from chronic inflammatory diseases such as leprosy, osteomyelitis, or rheumatoid arthritis, or it may be part of multiple myeloma (AL amyloid is found in myeloma-associated amyloid) or Waldenström’s macroglobulinemia. The ocular structures are usually spared.

3. Secondary localized amyloidosis (Fig. 7.15) may result from such chronic local inflammations of the conjunctiva and lids as trachoma and chronic nongranulomatous, idiopathic conjunctivitis, and blepharitis.

III. Histology

A. Amyloid appears as amorphous, eosinophilic, pale hyaline deposits free in the connective tissue, or around or in blood vessel walls. A nongranulomatous inflammatory reaction or, rarely, a foreign-body giant cell reaction or no inflammatory reaction may be present.

Amyloid may have a natural green positive birefringence both in unstained sections and in hematoxylin and eosin-stained sections. The green birefringence is enhanced by Congo red staining.

B. The material demonstrates metachromasia (polycationic dyes such as crystal violet change color from blue to purple), positive staining with Congo red, dichroism (change in color that varies with the plane of polarized light, usually from green to orange with rotation of polarizer), birefringence (double refraction with polarized light) of Congo red-stained material, and fluorescence with thioflavine-T.

Birefringence is the change in refractive indices with respect to light polarized in different directions through a substance. Dichroism is the property of a substance absorbing light polarized in a certain direction. When light is polarized at right angles to this direction, it is transmitted to a greater extent. In contrast to birefringence, dichroism can be specific for a particular substance. Dichroism can be observed in a microscope with the use of either a polarizer or an analyzer, but not both, because the dichroic substance itself (e.g., amyloid) serves as polarizer or analyzer, depending on the optical arrangement. Amyloid is only dichroic to green light.

C. Electron microscopically, amyloid is composed of ordered or disordered, or both, filaments that have a diameter of approximately 7.5 nm.

D. Amyloid proteins

1. Amyloid fibril proteins derived from immunoglobulin light chains are designated AL (see Chapter 12) and are found in primary familial amyloidosis and secondary amyloidosis associated with multiple myeloma and Waldenström’s macroglobulinemia (monoclonal gammopathies).

2. Other secondary amyloidoses show a tissue amyloid derived from a serum precursor (designated amyloid AA) or an amyloid that is a variant of prealbumin.

3. Another protein, protein AP, is found in all of the amyloidoses and may be bound to amyloid fibrils.

Cysts, Pseudoneoplasms, and Neoplasms

Choristomas

I. Epidermoid cyst—see Chapter 14.

II. Dermoid cyst—see Chapter 14.

Most limbal dermoids are solid and contain epidermal, dermal, and fatty tissue. Rarely, they may be cystic and may contain bone, cartilage, lacrimal gland, teeth, smooth muscle, brain, or respiratory epithelium.

III. Dermolipoma (Fig. 7.16)

A. Dermolipoma usually presents as bilateral, large, yellowish-white soft tumors near the temporal canthus and extending backward and upward.

B. It is a form of solid dermoid composed primarily of fatty tissue. Serial sections of the tumor must be made to find nonfatty elements such as stratified squamous epithelium and dermal appendages.

Nevus lipomatosus (pedunculated nevus) has been reported on the eyelid of an 11-year-old boy having an eyelid papule that had been present since birth and was gradually enlarging. Histologically, the lesion was polypoid in shape and consisted of mature adipocytes within the dermis and subconjunctival mucosa consistent with nevus lipomatosus.

VI. Epibulbar (episcleral) osseous choristoma (bone-containing choristoma of the conjunctiva) is usually located in the supratemporal quadrant (see Fig. 8.65) and may contain other choristomatous tissue as frequently as 10% of the time. The lesion may be attached to the underlying muscle or sclera.

Pseudocancerous Lesions

I. Hereditary benign intraepithelial dyskeratosis (HBID; Fig. 7.18; see Fig. 6.4A)

A. HBID is a bilateral dyskeratosis of the conjunctival epithelium associated with comparable lesions of the oral mucosa and inherited as an autosomal-dominant trait.

The disease is indigenous to family members of a large triracial (Native American, black, and white) isolate in Halifax County, North Carolina. Members of the family now live in other areas of the United States, so the lesion may be encountered outside North Carolina.

B. Clinically, irregularly raised, horseshoe-shaped, granular-appearing, richly vascularized, gray plaques are present at the nasal and temporal limbus in each eye. A whitish placoid lesion of the mucous membrane of the mouth (tongue or buccal mucosa) is also present.

C. There is duplication in chromosome 4 (4q35).

Corneal abnormalities may be found, especially stromal vascularization and dyskeratotic plaques of the corneal epithelium. The corneal plaques, like the conjunctival limbal plaques, invariably recur if excised.

D. Histologically, considerable acanthosis of the epithelium is present along with a chronic nongranulomatous inflammatory reaction and increased vascularization of the subepithelial tissue. A characteristic dyskeratosis, especially prominent in the superficial layers, is seen.

1. Papanicolaou stained cytologic preparations can be helpful in the diagnosis by demonstrating rounded squamous epithelial cells with dense homogeneous orange cytoplasm and hyperchromatic pyknotic or crenated nuclei.

II. Pseudoepitheliomatous hyperplasia (PEH; see Chapter 6)

A. PEH may mimic a neoplasm clinically and microscopically.

B. Epithelial hyperplasia and a chronic nongranulomatous inflammatory reaction of the subepithelial tissue, along with neutrophilic infiltration of the hyperplastic epithelium, are characteristic of PEH. PEH may occur within a pinguecula or pterygium and cause sudden growth that simulates a neoplasm.

C. Keratoacanthoma (see Chapter 6) may be a specific variant of PEH, perhaps caused by a virus, or more likely a low-grade type of squamous cell carcinoma.

III. Papilloma (squamous papilloma; Fig. 7.19)

A. Conjunctival papillomas tend to be pedunculated when they arise at the lid margin or caruncle, but sessile with a broad base at the limbus.

1. Papillomas are rare in locations other than the lid margin, interpalpebral conjunctiva, or caruncle.

2. Approximately one-fourth of all the lesions of the caruncle are papillomas.

Although inverted papillomas (schneiderian or mucoepidermoid papillomas) typically involve mucous membranes of the nose, paranasal sinuses, and lacrimal sac, they only occasionally involve the conjunctiva.

B. Human papillomavirus (HPV) types 6, 11, 16, 18, and 33 have been identified in conjunctival papillomas.

In subtropical Tanzania, where dysplastic lesions and neoplasms of the conjunctiva account for 2% of all malignant lesions, HPV-6/11, HPV-16, and HPV-18 characterize precancerous and squamous cell lesions of the conjunctiva. Co-infections are frequently observed. Higher signal intensity is observed in dysplasia grades 1 and 2 and in better-differentiated areas of the invasive component of conjunctival carcinoma compared to less-differentiated areas. Focal epithelial hyperplasia is rare and caused by HPV-13 or -32. Although thought to infect the oral mucosa exclusively, HPV-13 has been reported to cause multiple conjunctival papillomas in an otherwise healthy patient. p53 mutations in limbal epithelial cells, probably caused by ultraviolet irradiation, may be an early event in the development of some limbal tumors, including those associated with HPV.

C. Histologically, the fronds or finger-like projections are covered by acanthotic epithelium, tending toward slight or moderate keratinization. The fronds have a core of fibrovascular tissue.

Goblet cells are common in the papillomas, except those arising at the limbus. Although most papillomas are infectious or irritative in origin and have little or no malignant potential, occasionally one may develop into a squamous cell carcinoma.

IV. Oncocytoma (eosinophilic cystadenoma, oxyphilic cell adenoma, apocrine cystadenoma; Fig. 7.20)

A. Oncocytoma is a rare tumor of the caruncle.

1. Most commonly, the tumor presents as a small, yellowish-tan or reddish mass arising not from surface epithelium but, rather, from accessory lacrimal glands in the caruncle, especially in elderly women. It can also arise from the conjunctival accessory lacrimal glands, lacrimal sac, or eyelid.

2. High-frequency ultrasound of the lesion reveals low internal reflectivity and a cystic component. Multiple hypoechogenic tumor stroma components correlate with multiple cystic glandular structures on histopathologic examination.

3. Rarely, the tumor may undergo carcinomatous transformation.

B. Histologically, one or more cystic cavities are lined by proliferating epithelium, resembling apocrine epithelium (hence, apocrine cystadenoma).

V. Myxoma

A. Myxomas are rare benign tumors that resemble primitive mesenchyme and are often mistaken for cysts.

1. They have a smooth, fleshy, gelatinous appearance and are slow-growing.

2. Myxomas may be found in Carney’s syndrome, an autosomal-dominantly inherited syndrome consisting of myxomas (especially cardiac but also eyelid), spotty mucocutaneous (including conjunctiva) pigmentation (see Chapter 17), and endocrine overactivity (especially Cushing’s syndrome).

B. Histologically, the tumor is hypocellular and composed of stellate and spindle-shaped cells, some of which have small intracytoplasmic and intranuclear vacuoles.
The stroma contains abundant mucoid material, sparse reticulin, and delicate collagen fibers.

VI. Dacryoadenoma

A. Dacryoadenoma is a rare benign conjunctival tumor arising from metaplasia of the surface epithelium.

B. Histologically, an area of metaplastic surface epithelium with cuboidal to columnar cells invaginates into the underlying connective tissue, forming tubular and glandlike structures. Electron microscopy shows cells containing zymogen-type lacrimal secretory granules.

VII. Rarely, inverted follicular keratosis may arise in the conjunctiva.

Cancerous Epithelial Lesions

All such tumors may appear clinically as leukoplakia.1 Reported cases of neoplasms involving orbits containing ocular prostheses highlight the importance of a periodic thorough examination of such sockets.

I. In a review of 12,102 consecutive cases accessioned at an ocular pathology laboratory from 1993 to 2009, there were 273 (2.25%) conjunctival lesions, of which there were 86 (0.71%) epithelial tumors; 15 (17.4%) of the epithelial tumors were squamous cell papillomas. Among the ocular squamous neoplasia cases, 11.6% were actinic keratosis, 31.3% were conjunctival intraepithelial neoplasia with variable degrees of atypia, 17.4% represented carcinoma in situ, and 19.7% were squamous cell carcinomas. Only one case of each basal cell carcinoma and mucoepidermoid carcinoma was found.

A. Ki-67 labeling index, which is strictly associated with cell proliferation, is 46% in sebaceous gland carcinoma, 28% in squamous cell carcinoma, 20% in conjunctival intraepithelial neoplasia, 9% in pterygium, and 7% in normal conjunctiva. These findings suggest that Ki-67 labeling index may be useful for malignant tumor grading of ocular surface tumors.

B. Cell proliferation and apoptosis markers are altered in the development of conjunctival squamous cell papillomas and squamous cell carcinomas. In papillomas, p53 expression is observed in approximately 67%; Ki-67 in 31%; proliferating cell nuclear antigen in 98%; Bcl-2 in 53%; Bak in 62%; Bax in 69%; and Bcl-xl in 100%. In squamous cell carcinomas, p53 expression is observed in approximately 73%; Ki-67 in 18%; proliferating cell nuclear antigen in 73%; Bcl-2 in 45%; Bak in 91%; Bax in 91%; and Bcl-xl in 100%. Alterations in these cellular proliferation and apoptosis markers appear to be important events in cancer development.

C. The development of conjunctival squamous cell carcinoma from premalignant lesions is accompanied by the outgrowth of new conjunctival lymphatic vessels, termed tumor-associated lymphangiogenesis, which in turn is associated with an increased risk of local recurrence of conjunctival intraepithelial neoplasia and squamous cell carcinoma.

D. There seems to be considerable geographic variation in the association of HPV with conjunctival neoplasia. In Uganda, HPV (most commonly -5 and -8) was detected in 45% of conjunctival squamous cell carcinomas and 41% of dysplasia cases. In Germany, however, no specimens out of 31 cases of ocular squamous neoplasia were positive for HPV, and ultraviolet radiation was cited as an important risk factor for squamous neoplasia.

E. HIV infection, even in non-African countries such as the United States, is associated with an increased risk of conjunctival squamous cell carcinoma.

F. Exfoliative cytology examination has a 91% concordance in interpretation of conjunctival cytologic specimens as to the presence of dysplasia versus no dysplasia, but it is less useful (59% concordance) in grading the degree of dysplasia. It can be helpful in detecting dysplasia prior to surgical resection.

II. Carcinoma derived from the squamous cells of conjunctival epithelium

A. Conjunctival intraepithelial neoplasm (CIN; dysplasia, carcinoma in situ, intraepithelial carcinoma, intraepithelial epithelioma, Bowen’s disease, intraepithelioma; Figs. 7.21 and 7.22)

1. Clinically, it may appear as leukoplakia or a fleshy mass, usually located at or near the limbus. Occasionally, conjunctival squamous cell carcinoma may be pigmented, thereby clinically suggesting malignant melanoma. The papillomatous arrangement of blood vessels in such tumors may be helpful in clinically differentiating them from melanomas, even in the absence of leukoplakia.

2. Solar elastosis is found much more frequently in conjunctival squamous cell neoplasia patients than in control individuals.

3. Atopic eczema may be a risk factor for squamous cell carcinoma of the conjunctiva, and its development may be related to T-cell immunologic dysfunction.

4. High-frequency ultrasonography can be used to evaluate the tumor thickness, shape, internal reflectivity, and extent of conjunctival intraepithelial neoplasia and squamous cell carcinoma.

Human immunodeficiency virus (HIV) infection should be considered in any patient younger than 50 years of age who has a conjunctival intraepithelial neoplasia.

5. Histology

a. The lesions range from mild dysplasia with nuclear atypia, altered cytoplasmic-to-nuclear ratios, and abnormal cell maturation confined to the basal third of the epithelium, to full-thickness replacement of the epithelium by atypical, often bizarre and pleomorphic epithelial cells.

b. Dyskeratotic epithelial cells may be seen. Rarely, mucoepidermoid differentiation can be seen in the neoplasm.

c. The involved epithelial area is thickened and sharply demarcated from the contiguous, normal-appearing conjunctival epithelium. The thickening usually ranges from approximately two to five times normal thickness, but it may be greater in malignant transformation of papillomas.

d. Polarity of the epithelium is lost, and mitotic figures commonly are found.

e. The basement membrane of the epithelium is intact, and no invasion of the subepithelial tissue occurs.

f. Conjunctival squamous cell carcinoma intensely expresses immunoreactivity for the tyrosine kinase EGF receptor. Studies involving the induction of apoptosis in serum-deprived cultured conjunctival epithelial cell have demonstrated that EGF and retinoic acid play key roles in the maintenance of the ocular surface.

g. Conjunctival intraepithelial neoplasia and squamous cell carcinoma are associated with preferential expression of p63 in the immature dysplastic epithelial cells. The staining for p63, which is a homolog of the tumor suppressor gene p53, is not correlated with MIB-1 expression and, therefore, appears not to be linked to cell proliferation.

h. Regardless of patient race, pigmentation of conjunctival squamous cell carcinoma may occur (Fig. 7.23). Such pigmented lesions are uncommon, comprising 1.6% of lesions. Pigmented dendritic melanocytes are the source of the pigment, which may be “donated” to squamous cells, resulting in their having intracellular melanin in some cases.

Never clinically, but occasionally histologically, CIN may resemble superficially the intraepithelial carcinoma of the skin described by Bowen (Bowen’s disease) or the intraepithelial carcinoma of the glans penis described by Queyrat (erythroplasia of Queyrat). Both entities are specific clinicopathologic entities, and their terms should be restricted to their proper use, which never includes carcinoma in situ of the conjunctiva or any conjunctival neoplasm.

B. Squamous cell carcinoma with superficial invasion (see Fig. 7.22B)
In addition to the epithelial changes of CIN, invasion by the malignant, pleomorphic, atypical squamous epithelial cells occurs through the epithelial basement membrane into the superficial subepithelial tissue.

Rarely, squamous cell carcinoma with superficial (micro) stromal invasion can arise primarily in the cornea (squamous cell carcinoma of the cornea) without extension to the corneoscleral limbus.

C. Squamous cell carcinoma with deep invasion (see Fig. 7.22C)
In addition to the epithelial changes of CIN, there is invasion by the malignant squamous epithelial cells through the epithelial basement membrane deep into the subepithelial tissue or even into adjacent structures.

Spindle-cell carcinoma is a rare variant of squamous cell carcinoma and may arise from the conjunctiva. Positive staining with cytokeratin and epithelial membrane antigen markers is helpful in differentiating the variant from other spindle-cell tumors, such as amelanotic melanoma, malignant schwannoma, fibrosarcoma, leiomyosarcoma, and malignant fibrous histiocytoma. Malignant fibrous histiocytoma rarely arises in the conjunctiva.

D. Squamous cell carcinoma with metastasis
All the features of squamous cell carcinoma with deep invasion are involved, plus evidence of metastasis. Metastatic squamous cell carcinoma may be an atypical presentation of HIV infection.

E. Basaloid squamous cell carcinoma (Fig. 7.24)

1. Usually involves the larynx, hypopharynx, tonsils, and base of tongue, where it has a much more aggressive character than the usual squamous cell carcinoma, but it may also occur in the conjunctiva.

2. It is composed of small crowded cells with scant cytoplasm and hyperchromatic.

3. Ultrastructure is characterized by the presence of rare tonofilaments and varying numbers of desmosomes.

4. Cells have a nesting, lobular, and trabecular arrangement.

5. Small cystic spaces contain either loose stellate granules or replicated basal lamina arranged in parallel stacks or globoid masses.

6. Basaloid cells in lobules may have peripheral nuclear palisading and high mitotic activity and may mimic multiple varieties of carcinoma.

III. Carcinoma derived from the basal cells of conjunctival epithelium

Basal cell carcinoma rarely arises from the conjunctiva or caruncle.

The lid differs from the conjunctiva in being a site of preference for basal cell carcinoma.

IV. Carcinoma derived from the mucus-secreting cells and squamous cells of conjunctival epithelium

Mucoepidermoid carcinoma (Fig. 7.25) is a rare conjunctival tumor characteristically composed of mucus-secreting cells intermixed with epidermoid (squamous) cells.

Mucoepidermoid carcinoma can also arise from the caruncle. A third type of cell, called intermediate or basal cell, may also be found.

A. Some tumors show a predominance of epidermoid cells, whereas others have mainly mucus-secreting cells.

B. The tumors appear to be aggressive locally and tend to recur rapidly after excision; a wide local excision is therefore recommended.

C. Histologically, lobules of tumor cells show a variable admixture of epidermoid and mucus-secreting cells.
Histochemical stains for mucin are most helpful in confirming the diagnosis.

Pigmented Lesions of the Conjunctiva

See section Melanotic Tumors of Conjunctiva in Chapter 17.

Laugier–Hunziker syndrome is a rare acquired hyperpigmentation of the oral mucosa and lips, which is often associated with longitudinal melanonychia (black pigmentation of the nails). It may also be associated with conjunctival and penile pigmentation. Histopathologic examination demonstrates basal epithelial melanosis, moderate acanthosis, and superficial pigmentary incontinence. Electron microscopic examination reveals increased number of normal-appearing melanosomes inside basal keratinocytes and dermal melanophages.

Stromal Neoplasms

I. Angiomatous—see discussions of hamartomas and vascular mesenchymal tumors in Chapter 14.

II. Pseudotumors, lymphoid hyperplasia, lymphomas, and leukemias (Fig. 7.26)—see discussions of tumors of the reticuloendothelial system, lymphatic system, and myeloid system in Chapter 14.

A. Lymphoproliferative lesions represent 25–33% of acquired subepithelial conjunctival lesions that are excised or biopsied in patients older than 15 years of age.

B. Extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) constitutes approximately 88% of all lymphomas involving the ocular adnexa and tends to appear in patients with a history of autoimmune disease or chronic inflammatory disorders (it has been reported in a child).

1. Rarely, MALT may arise in Tenon’s capsule (these lesions respond well to conventional treatment; however, there is a high rate of recurrence).

2. MALT lymphoma usually is CD5-negative; however, CD5-positive cases have been reported sometimes associated with trisomy 3. The presence of accompanying lymphoepithelial lesions also may be found.

3. Infection with Chlamydophila psittaci has been associated with conjunctival MALT lymphoma. The organism has been detected in 75% of lymphoma tissue, in 50% of conjunctival swabs and/or peripheral blood mononuclear cells, and viability and infectivity of the organism by growth in culture has been documented in 25% of patients. Others have not had similar results and have suggested a geographic heterogeneity as underlying such variability.

4. An association between Helicobacter pylori infection and localized conjunctival MALT lymphoma has been suggested but has not been confirmed.

At least three different site-specific chromosomal translocations involving the nuclear factor-κB have been implicated in the development and progression of MALT lymphoma. The most common such translocation is t(11;18)(q21;q21), resulting in the fusion of the cIAP2 region on chromosome 11q21 with the MALT1 gene on chromosome 18q21, and is said to be involved in more than one-third of cases. In gastric MALT lymphoma, t(11;18)(q21;q21) is significantly associated with infection by CagA-positive strains of Helicobacter pylori, and eradication of the organism is standard therapy for all H. pylori-positive gastric MALT lymphomas. Oxidative damage may play a role in the development of this translocation. Translocation t(14;18)(q32;q21) is also commonly found in this disorder, and the specific translocation varies considerably with the primary location of the disease. MALT lymphoma has also been found in a patient with adult inclusion conjunctivitis. BCL2-IgH [t(14;18)] gene rearrangement has been found in conjunctival MALT lymphoma.

5. CD43+ ocular lymphomas are associated with a higher rate of subsequent distant recurrence and rate of lymphoma-related death.

6. Uncommonly, conjunctival B-cell lymphoma may present as an ulcerating tarsal conjunctival mass.

The spontaneous regression of a large B-cell lymphoma involving the conjunctiva and orbit has been reported. Mantle cell lymphoma has presented as a marked follicular conjunctivitis in both eyes with a nodal mass in the right upper eyelid and nuchal lymphadenopathy. The diagnosis was made on conjunctival biopsy.

C. Although rarely found in the conjunctiva, T-cell lymphoma must be considered in the differential diagnosis of gelatinous lesions of the conjunctiva. It is characterized by positive staining with CD45 RO (T-cell marker) and negativity with CD20 (B-cell marker). In addition, positivity for T-cell receptor gene rearrangement with clonality confirms the diagnosis.

D. Lethal midline granuloma associated with natural killer (NK)/T-cell lymphoma and Epstein–Barr virus infection has presented involving the conjunctiva.

E. Lymphoproliferative lesions of the conjunctiva can be associated with Epstein–Barr virus infection and can simulate lymphoma.

F. T-cell prolymphocytic leukemia, a rare and very aggressive hematological neoplasm, has presented with bilateral perilimbal conjunctival infiltrates, in which the diagnosis was confirmed on histo­pathologic examination. Conjunctival involvement has accompanied uveal (including anterior uveitis), palpebral, and orbital invasion by adult T-cell leukemia.

III. Juvenile xanthogranulomas—see Chapter 9.

IV. Neural tumors—see discussion of neural mesenchymal tumors in Chapter 14.

V. Fibrous tumors—see discussion of fibrous–histiocytic mesenchymal tumors in Chapter 14.

VI. Leiomyosarcoma and rhabdomyosarcoma—see discussion of muscle mesenchymal tumors in Chapter 14.

A. Rarely, rhabdomyosarcoma may present as a conjunctival lesion without orbital extension.

VII. Metastatic

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