Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

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.

IV. Xeroderma pigmentosum—see p. 172 in Chapter 6.

V. Ichthyosis congenita—see p. 171 in Chapter 6.

VI. Molluscum contagiosum—see p. 176 in Chapter 6.

VII. Dermatitis herpetiformis, epidermolysis bullosa, erythema nodosum, and many others may show conjunctival manifestations.

Vitamin A Deficiency: Bitot’s Spot

See p. 276 in Chapter 8.

Sjögren’s Syndrome

See p. 274 in Chapter 8 and p. 533 in Chapter 14.

Skin Diseases

I. Erythema multiforme (Stevens–Johnson syndrome)—see

p. 181 in Chapter 6.

II.Atopic dermatitis

III. Rosacea—see p. 176 in Chapter 6.

DEGENERATIONS

Xerosis

I.Xerosis (dry eyes; Fig. 7.11) owing to conjunctival disease may result from keratoconjunctivitis sicca (Sjögren’s syndrome), ocular pemphigoid, trachoma, measles, vitamin A deficiency, proptosis with exposure, familial dysautonomia, chemical burns, and erythema multiforme (Stevens–

Johnson syndrome).

II.Histologically, the epithelium undergoes epidermidalization with keratin formation, and the underlying subepithelial tissue frequently shows cicatrization.

Pterygium

See p. 277 in Chapter 8.

Pinguecula

I.Pinguecula (Fig. 7.12) is a localized, elevated, yellowishwhite 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 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.

T ehsubepithelial dense concretions stain positively for lysozyme.

Lipid Deposits

I.Biomicroscopic examination of peripheral bulbar conjunctiva and episcleral tissue, especially in the region of the palpebral fissure, often reveals lipid globules.

A.The globules, which increase with age, vary from 30 to

80 nm in diameter, but tend to be fairly uniform in size in each patient.

B.The deposits assume two basic patterns: most often, multiple globules lying adjacent to blood vessels; and sometimes globules occurring in isolated foci unrelated to blood vessels.

C.Subconjunctival and episcleral lipid deposits are asymptomatic (except for rare granulomatous response to the lipids) and occur in approximately 30% of patients.

II.Histologically, lipid material may be present free within extracellular spaces in the subepithelial conjunctival and episcleral loose connective tissue or, rarely, a granulomatous inflammatory process may surround it.

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, p. 296 in Chapter 8, and p. 488 in Chapter 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 lambda 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).

b.Lambda light chains contain six variable-region subgroups.

c.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 p. 488 in 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 p. 488 in

Chapter 12)

C. Localized (localized nodular amyloidosis; see also p. 296 in 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: 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 p. 283 in 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)

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.

The eyelids may show characteristic multiple purpuric lesions in secondary systemic amyloidosis, especially in multiple myeloma (Fig. 7.13).

3.Secondary localized amyloidosis (Fig. 7.14) may result from such chronic local inflammations of the conjunctiva and lids as trachoma and chronic nongranulomatous, idiopathic conjunctivitis, and blepharitis.

The condition is not as common as primary local amyloidosis.

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 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 p. 488 in

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.

Conjunctivochalasis

I.Conjunctivochalasis is usually found in older individuals and consists of an elevation of the bulbar conjunctiva along the lateral or central lower-lid margin. It may also involve the upper bulbar conjunctiva. It is a cause for tearing, and may worsen dry-eye symptoms. A possible mechanism for its development is as a result of mechani-

cal forces between the lower eyelid and conjunctiva interfering with lymphatic flow which, when chronic, may result in lymphatic dilatation and, eventually, conjunctivochalasis.

II.The most common histopathologic findings are elastosis or chronic nongranulomatous inflammation. Additionally, microscopic lymphangiectasia is typically present.

CYSTS, PSEUDONEOPLASMS,

AND NEOPLASMS

Choristomas

I.Epidermoid cyst—see p. 540 in Chapter 14.

II.Dermoid cyst—see p. 540 in 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. 7.15)

A.Dermolipoma usually presents as bilateral, large, yel- lowish-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.

Frequently, serial sections of the tumor must be made to find nonfatty elements such as stratified squamous epithelium and dermal appendages.

IV. 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.

V.Epibulbar (episcleral) osseous choristoma (bonecontaining choristoma of the conjunctiva) is usually located in the supratemporal quadrant (Fig. 8.60) and may contain

other choristomatous tissue as frequently as 10% of the time. The lesion may be attached to the underlying muscle or sclera.

Hamartomas

I. Lymphangioma—see p. 545 in Chapter 14.

II.Hemangioma—see p. 544 in Chapter 14. III. Phakomatoses—see p. 29 in Chapter 2.

Cysts

I. Cysts of the conjunctiva (Fig. 7.16) may be congenital or acquired, with the latter predominating.

II.Acquired conjunctival cysts are mainly implantation cysts of surface epithelium, resulting in an epithelial inclusion cyst. Other cysts may be ductal (e.g., from accessory lacrimal glands) or inflammatory.

III.Histologically, the structure depends on the type of cyst.

A.Epidermoid and dermoid cyst—see p. 540 in Chapter 14.

B.Epithelial inclusion cysts, lined by conjunctival epithelium, contain a clear fluid.

C.Ductal cysts (e.g., Wolfring dacryops) are lined by a double layer of epithelium and contain a PAS-positive material.

D.Inflammatory cysts contain polymorphonuclear leukocytes and cellular debris.

Pseudocancerous Lesions

I.Hereditary benign intraepithelial dyskeratosis (HBID; Fig.

7.17; see Fig. 6.4A)

A.HBID is a bilateral dyskeratosis of the conjunctival epithelium associated with comparable lesions of the

A

C

of the nose, paranasal sinuses, and lacrimal sac, they only occasionally involve the conjunctiva.

B.Human papillomavirus (HPV) types 6, 11, 16, 18, and

33have been identified in conjunctival papillomas. Moreover, 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-di erentiated areas of the invasive component of conjunctival carcinoma compared to less-di erentiated areas.

1.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

B

Fig. 7.18 Papilloma. A, A large sessile papilloma of the limbal conjunctiva is present. B, Histologic section shows a papillary lesion composed of acanthotic epithelium with many blood vessels going into the individual fronds, seen as red dots in the clinical picture in A. The base of the lesion is quite broad. C, Increased magnification shows the blood vessels and the acanthotic epithelium. Although the epithelium is thickened, the polarity from basal cell to surface cell is normal and shows an appropriate maturation. (A, Courtesy of Dr. DM Kozart.)

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. 7.19)

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 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.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).

1.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.

C

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 p. 668 in 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.

T ehstroma 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.

C.Electron microscopy shows cells containing zymogen-

type lacrimal secretory granules.

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

Potentially Precancerous Epithelial Lesions

I. Xeroderma pigmentosum—see p. 172 in Chapter 6. II. Other actinic keratoses—see p. 194–196 in Chapter 6.

Cancerous Epithelial Lesions

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

I.From the 1960s to the 1980s, the incidence of cutaneous squamous cell carcinoma rose 2.6-fold in men and 3.1-fold in women.

A.The rising incidence is probably attributable to increased voluntary exposure to sun and the depletion of the ozone layer.

B.An emerging epidemic of squamous cell carcinoma seems to be occurring.

C.Ki-67 labeling index, which is strictly associated with cell proliferation, is 46% in sebaceous gland carcinoma;

*Leukoplakia is a clinical, descriptive term, not a clinical or a microscopic diagnosis. Histologieally lesions that present as leukoplakia may range from pinguecula to frank squamous cell carcinoma. The leukoplakic or white, shiny appearance is caused by keratinization of the normally nonkeratinized conjunctival epithelium.

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.

D.Cell proliferation and apoptosis markers are altered in the development of conjunctival squamous cell papil-

lomas 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.

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 7.20 and 7.21)

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 di erentiating 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-thick-

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