Cryptophthalmos (from the Greek kryptos meaning hidden and ophthalmos meaning eye) is a unilateral or more often bilateral congenital anomaly characterized by abnormal eyelids and eye covered by intact skin. Typically, the conjunctival sac is absent and the eye(s) is microphthalmic. Cryptophthalmos may be part of Fraser’s syndrome, an entity defined by genital malformation and occasional malformation of the nose, ears, larynx, and renal system [3]. Fraser’s syndrome is an autosomal recessive disease linked to the FRAS1 and FREM2 genes and mapped to chromosome 4q21 [4]. Recently, mutation of the GRIP1 gene has also been associated with Fraser’s syndrome [5]. The incidence has been estimated to 0.043 in 10,000 live births [6].

Coloboma of the lid typically involves the palpebral conjunctiva as part of the defect. This congenital malformation may occur in association with an epibulbar choristoma and is sometimes a feature of the Goldenhar and Treacher Collins syndromes [7].

Hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber disease) is characterized by systemic telangiectasia that may appear in the (often palpebral) conjunctiva and give rise to recurrent hemorrhages [1]. The Sturge–Weber syndrome (so-called nevus flammeus or angiomatosis associated with the trigeminal nerve branches) may have an ocular component characterized by diffuse choroidal hemangioma (essentially a hamartomatous malformation of the choroid) and episcleral and conjunctival vascular malformation. Importantly, children with Sturge–Weber syndrome may develop glaucoma and a number of other ocular complications [8]. Lymphangiectasia and lymphangioma are congenital vascular lymphatic malformations that may be cystic and circumscribed or more extensive and part of an orbital lymphatic malformation. These lesions may appear in any part of the conjunctiva, but are most common on the bulbar conjunctiva away from the limbus [9]. Typically, the cyst-like spaces are filled with clear fluid, but may sometimes, in association with trauma or without any apparent cause, be filled with blood and appear as hemorrhagic lymphangiectasia.

Choristomas contain ordinary cells not normally present on the site often as a result from a developmental abnormality. Conjunctival choristomas include the limbal dermoid often associated with Goldenhar’s syndrome. The limbal dermoid consists of hair shafts and sebaceous gland-like structures, believed to be displaced as a result of anomalous lid development. It typically occurs as a tan or pale dome-shaped structure at the inferior or temporal limbus [1]. Lipodermoids (alternatively termed dermolipoma) tend to present in the temporal periphery of the conjunctiva. These lesions are choristomas containing abundant fat (in contrast to limbal dermoids) and may fuse imperceptibly with the orbital fat. If excised they may present a surgical challenge because of the lack of a distinct cleavage plane. The rare epicorneal lipodermoid occurs centrally on the cornea and, in contrast to the limbal dermoid, appears not be associated with Goldenhar’s syndrome [10]. Complex choristomas typically consist of several cellular components, e.g., cartilage, bone (osseous choristoma), or lacrimal gland tissue (ectopic lacrimal glands) [11].

Acute conjunctivitis is usually bilateral and features vascular dilation, stromal edema, and abundant polymorphonuclear leukocytes. Inflammation may sometimes be extensive and cause the lining conjunctival epithelium to be ulcerated. Rarely, the acute inflammation induces stromal necrosis. Typically, acute conjunctivitis is caused by any of a large number of viral agents. Epidemic keratoconjunctivitis is associated with adenovirus infection and is an aggressive, highly contagious subtype including some distinctive clinical characteristics. This variant may be associated with tarsal membrane formation [12]. Disease usually resolves without sequelae, but corneal scarring may develop.

Chronic conjunctivitis has nonspecific characteristics like a mild to moderately increased number of stromal lymphocytes and stromal edema. Long-standing disease may generate additional findings. These include stromal fibrosis, depletion of goblet cells, and epithelial infoldings that may generate inclusion cysts that sometimes include small calcifications [1]. Papillae of the tarsal conjunctiva may also be present. This is a nonspecific finding that may, however, also be present in vernal conjunctivitis and giant papillary conjunctivitis [1]. Follicles are composed of accumulation of lymphoid tissue sometimes with a germinal center. They appear as small nodules, approximately 1 mm in diameter, and typically present in the fornix. The causes of chronic conjunctivitis include a host of infectious agents (Fig. 2.2), local irritants, chemical compounds, topical medications, foreign bodies, and even neoplasms [1]. Some agents cause a distinct appearance like the bilateral epithelial hyperplasia with follicles and papilla and in particular extensive whitish scarring seen in the upper tarsal conjunctiva after long-standing Chlamydia trachomatis infection. Over eight million people are estimated to have trachomatous trichiasis as a result of scarring leading to entropion, and trachoma of the eye remains the leading infectious blinding disease worldwide [13, 14].

Granulomatous conjunctivitis is uncommon and often unilateral. Pertinent histopathological features include chronic inflammation associated with caseating or non-caseating granulomas. Granulomatous conjunctivitis may arise in combination with systemic disease including Wegener’s granulomatosis and sarcoidosis [1, 15]. Occasionally, foreign bodies such as the hair shafts of caterpillars and infectious disease like onchocerciasis, blastomycosis, and tuberculosis may initiate granulomatous conjunctivitis [16–18]. Also, topical therapy including the use of preservatives has been associated with cicatrizing granulomatous conjunctivitis [19]. Secondary involvement of the tarsal conjunctiva may follow meibomian gland inflammation with or without the presence of a chalazion [20]. Rarely, cat-scratch disease may cause conjunctival involvement as a feature of the oculoglandular syndrome of Parinaud [1].

Allergic conjunctivitis is very common in the Western world (reportedly occurring in up to 15–20 % of the population) [21]. It typically presents as seasonal or perennial conjunctivitis in children and adolescents associated with itching. Vernal keratoconjunctivitis is a subtype, more common in the tropics than temperate climates, and presents in a limbal and palpebral form that may coexist. The limbal form is characterized by the so-called Tranta’s dots, but may also include giant papillae of the tarsal conjunctiva. Disease typically resolves by age 20 years. Atopic keratoconjunctivitis is another variant, often associated with atopic dermatitis. Histopathologically, the entity may feature giant papillae, but more commonly include conjunctival scarring. The conjunctiva is also prone to contact allergy caused by any of a range of low molecular weight substances. This reaction to a local irritant is cell mediated in contrast to the allergic variants listed above which are all IgE mediated [22].

Giant papillary conjunctivitis is caused by irritants and no longer believed to be an allergic reaction. These irritants include contact lenses, limbal sutures, ocular prostheses, and limbal dermoids [23, 24]. The histopathological features include the typical giant papillae of the upper tarsal conjunctiva (Fig. 2.3) and the presence of mast cells, basophils, and eosinophils. There is, however, no increase of IgE in the tear film as in true allergic conjunctivitis [22].

Hypersensitivity (phlyctenular) conjunctivitis is caused by proteins released by bacteria. In the Western world, this reaction to the eyelids and tarsal conjunctiva is often caused by hypersensitivity to staphylococcal infection. In a tropical setting, however, there is a significant association with coexisting tuberculosis [25]. Clinically, this entity is characterized by 2–3 mm whitish nodules composed of subepithelial acute and chronic inflammatory cells. These may cause an epithelial ulceration that eventually resolves by scarring [1].

Conjunctivitis may be associated with systemic disease, often dermatological disorders, like atopic keratoconjunctivitis (see above under allergic conjunctivitis), acne rosacea, mucous membrane pemphigoid, erythema multiforme (Stevens–Johnson syndrome), and epidermolysis bullosa [1]. Acne rosacea is a prevalent skin disease of middle-aged adults which frequently (58–72 %) is associated with manifestation in the eyelids and ocular surface [26]. The etiology and pathogenesis remain largely unknown. Skin involvement includes erythema, telangiectasia, papules, pustules, and phymatous changes in the cheeks, nose, chin, and central forehead. Changes may, however, be subtle, and acne rosacea may remain undiagnosed for prolonged periods of time. In some 20 % of patients, symptoms of ocular rosacea may precede skin symptoms [27]. Clinical signs suggestive of ocular rosacea include conjunctival and eyelid telangiectasia, eyelid and periocular edema, anterior blepharitis, and meibomian gland dysfunction [26]. Histopathologically, there is chronic conjunctivitis sometimes with the formation of papillae [27]. Disease intensity is variable, but keratitis and cicatrizing conjunctivitis may ensue [28]. Ocular pemphigoid (cicatricial pemphigoid) is a bilateral, albeit asymmetrical, autoimmune disease of the middle-aged and elderly. Diagnosis is made by immunofluorescent studies on conjunctival biopsies demonstrating basement membrane linear deposits of IgG, IgA, IgM, and complement 3 (C3) [29]. Sensitivity with this technique has been reported to range from 20 to 67 %, and a rebiopsy and/or additional techniques may be considered when a negative result is obtained in clinically suspicious disease. Standard histopathology is rarely conclusive often showing nonspecific features like subepithelial inflammation with lymphocytes, neutrophils, and histiocytes and reduced number of goblet cells. Occasional necrosis is accompanied by extensive stromal scarring. The characteristic subepithelial bullae are often not present or sometimes confused with the intraepithelial blisters occurring in pemphigoid. Ocular pemphigoid often runs an aggressive course and is a potentially blinding disease. A comprehensive review is available elsewhere [29].

Erythema multiforme (toxic epidermal necrolysis) and Stevens–Johnson syndrome are two of a group of acute blistering mucocutaneous disorders which often affects the conjunctiva [1]. Initiating events are usually drugs like allopurinol, anticonvulsants, and nonsteroidal anti-inflammatory drugs. Possibly, toxic epidermal necrolysis and the Stevens–Johnson syndrome are at two ends of a spectrum of disease. The average reported mortality for Stevens–Johnson syndrome is 1–5 % and 20–25 % for toxic epidermal necrolysis [30]. Disease may be preceded by fever, arthralgia, and malaise [1]. Clinically, the mucocutaneous lesions that follow are bilateral, multiple forms of vesicles and bullae combined with epidermal erosion (scalding). Histopathological examination of a skin biopsy reveals full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis [30]. Scarring of the conjunctiva after healing may be extensive [1].

Epidermolysis bullosa is a rare, blistering mucocutaneous disease of autoimmune origin which may cause cicatrizing conjunctivitis. This entity is actually a heterogeneous group of disorders inherited in a dominant or recessive pattern. Epidermolysis bullosa disorders are caused by mutations of the structural proteins in the epidermis or dermoepidermal junction [31]. Currently, more than 1,500 different mutations in 17 different genes have been identified [32]. Diagnosis is made by a skin biopsy followed by immunofluorescence antigen mapping [31]. Transmission electron microscopy can detect the exact epidermal level of blistering and hence help to categorize disease into one of four groups now including more than 30 different subtypes. Signs of skin disease are often present shortly after birth and may be associated with involvement of the conjunctiva and other mucous membranes. Conjunctival vesicles, symblepharon, and chronic blepharoconjunctivitis as well as corneal involvement are hallmarks of ocular disease [1]. Intravenous immunoglobulin therapy may reverse the clinical course and improve ocular disease [33]. Disorders of the epidermolysis bullosa group are also candidates for protein replacement and gene therapy trials [34].

Ligneous conjunctivitis is a misnomer as the inflammation is secondary to extensive fibrin deposits, typically presenting in the upper tarsal conjunctiva. The surface epithelium is markedly thinned and atrophic or simply eroded. The surface is then covered by pseudomembranes largely consisting of cellular debris, fibrin, and polymorphonuclear leukocytes (Fig. 2.4). Ligneous conjunctivitis is caused by any of a range of mutations of the plasminogen gene. This causes functional plasminogen deficiency ultimately resulting in reduced fibrin clearance. Ligneous conjunctivitis may be associated with similar disease in, e.g., the mucous membranes of the airways and female genital tract [35].

Thermal injuries may be caused by foreign bodies, exposure to cooled or heated air, flames, or fluids. Sometimes damage is iatrogenic, e.g., after the use of the triple freeze–thaw technique during removal of conjunctival tumors. The thermal response includes an initial phase of tissue destruction, an interval reactive phase, and a period of tissue repair [1]. Minor thermal injuries are typically limited to the conjunctival epithelium. Migration of peripheral epithelial cells then heals the ulceration with no scarring. Deeper injuries involve the stromal connective tissue and may cause a coagulation necrosis. The healing process will be prolonged and may result in significant scarring [1]. The extent of chemical injuries depends on exposure time and the ability to penetrate the conjunctival epithelium. Histopathologically, chemical injuries to the conjunctiva mimic the three phases listed above. Alkali burns are particularly feared, and late-phase excessive scarring may result in symblepharon and trichiasis secondary to entropion formation. Techniques to repair the ocular surface after both thermal and chemical injuries have much improved in recent years and include limbal stem cell grafting and amniotic membrane transplantation [36].

Aberrant wound healing may result in a vascularized, hypertrophic scar that mimics the appearance of a pterygium, but usually lack the stromal elastosis seen in pterygia. This scar may encroach on the corneal surface like a pterygium. Excessive wound healing may also cause a so-called pyogenic granuloma. This rapidly growing, protruding lesion is histologically defined by vascularized, edematous granulation tissue with abundant inflammatory cells (Fig. 2.5). The lining epithelium can be eroded, and pyogenic granuloma may bleed intermittently. Usually, an underlying lesion like a chalazion or a history of trauma, e.g., previous surgery, can be identified. An inclusion cyst is not an infrequent finding in the conjunctiva following trauma or surgery (Figs. 2.6 and 2.7). These cysts derive from epithelial cells being displaced into the stroma and then proliferating into stromal cysts. Inclusion cysts may reach a significant size. Usually translucent, they may contain cellular debris and chronic inflammatory cells. Retained foreign bodies may be embedded in the conjunctival stroma and then elicit a mild foreign body reaction with the presence of giant cells of the foreign body type (see below under granulomatous conjunctivitis). Rarely, pigment may dissolve and cause conjunctival pigmentation that may simulate a melanocytic neoplasia (see below under Sect. 2.7.5).

Conjunctival xerosis (drying of the conjunctiva) may be congenital (very rare) or acquired and then usually associated with vitamin A deficiency or Sjögren’s syndrome (keratoconjunctivitis sicca). Moreover, conjunctival xerosis may present following ectropion, proptosis, lacrimal gland dysfunction, and post-radiotherapy. Significant xerosis leads to metaplasia of the conjunctival epithelium with epidermalization including rete ridge formation and loss of goblet cells. The stroma displays abundant chronic inflammatory cells, blood vessel dilation, and vascular congestion [1]. Vitamin A deficiency remains a significant public health problem and globally causes a million instances of premature deaths and blindness every year [37]. Sjögren’s syndrome is still the preferred term used for the drying of the cornea and conjunctiva initially associated with polymyalgia rheumatica, but later with other connective tissue disorders like rheumatoid arthritis, scleroderma, and systemic lupus erythematosus [1]. The xerosis in Sjögren’s syndrome may affect mucosa at nonocular sites like the nasal, oral, and genital mucosa. Sjögren’s syndrome is presumably an autoimmune disorder.

The pingueculum is a circumscribed nodular yellowish lesion appearing nasally or temporally or both at the perilimbal conjunctiva in the interpalpebral fissure. The histopathological features include significant stromal collagen degradation (sometimes termed elastoid degeneration although there is no clear evidence that collagen has been replaced by elastin fibers), stromal hypervascularization, and edema. The pterygium appears as a flat scar-like tissue extending onto the corneal surface from the nasal conjunctiva and is usually clinically distinct from the pinguecula. The histopathological appearance is, however, quite similar to the pinguecula, apart from vascularization being more common and prominent in a pterygium. Both lesions are more prevalent in the elderly and in a tropical setting. For this reason and because of the histopathological appearance, both lesions are regarded as actinic, presumably caused by excessive exposure to ultraviolet radiation. When a pterygium extends onto the cornea, it may need to be surgically removed. Traditionally, this has been associated with frequent recurrence, but recent techniques using no sutures or intraoperative topical mitomycin have reduced this [38, 39].

Conjunctival amyloidosis is relatively uncommon and most often occurs as primary localized amyloidosis without systemic involvement [40]. Rarely, conjunctival amyloid deposits may be the first sign of systemic amyloidosis [41]. Typically, amyloid deposits are circumscribed, yellowish-pink, subepithelial mass-like lesions. Clinical features may also include blepharoptosis and recurrent subepithelial conjunctival hemorrhage. Biopsy will reveal subepithelial amyloid deposits that show apple green birefringence under polarized light and stain positive with the Congo stain (Fig. 2.8). Conjunctival amyloid deposits may show intrinsic vascularization [40]. Amyloidosis is caused by deposits of a group of abnormally folded proteins. In localized amyloidosis, deposits occur at the site of protein synthesis, and in systemic disease, deposits occur distant to the site of protein secretion. The reason for the protein misfolding that generates insolvable cross β-sheet structures is unknown, but may involve a combination and/or environmental factors [42]. Amyloidosis may be secondary to renal disease, inflammatory bowel disease, and malignancies, notably myeloma.