Skin and Lacrimal Drainage System

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6

Skin and Lacrimal Drainage System

Skin

Normal Anatomy (Figs. 6.1 and 6.2)

Epidermis

Lid skin is quite thin.

Dermis

The dermis is sparse, composed of delicate collagen fibrils, and contains the vasculature and epidermal appendages, sebaceous glands, apocrine and eccrine sweat glands, and hair complexes.

Subcutaneous Tissue

The subcutaneous layer is mostly composed of adipose tissue.

Terminology

Orthokeratosis and Parakeratosis

I. The stratum corneum (keratin layer) is thickened.

Hyperkeratosis means “increased scale” and includes both orthokeratosis and parakeratosis. In orthokeratosis, a thick granular layer is found because the epidermal cells slowly migrate upward; when the migration upward is rapid, no granular cells are seen and parakeratosis results. Orthokeratosis is hyperkeratosis composed of cells that have complete keratinization and no nuclear remnants, whereas parakeratosis is hyperkeratosis that shows incomplete keratinization in which nuclei are retained in the cells of the stratum corneum. Orthokeratosis and parakeratosis often exist in the same lesion (Fig. 6.3A).

II. Orthokeratosis commonly is seen in verruca and the scaly lesions such as actinic and seborrheic keratoses.

III. Parakeratosis is characteristic of psoriasis and other inflammatory conditions (e.g., seborrheic keratosis).

Bulla

I. A bulla is a fluid-filled space in or beneath the epidermis (see Fig. 6.5).

Spongiosis is fluid accumulation between keratinocytes (intercellular edema), which may lead to cleft or vesicle formation. It is commonly seen in inflammatory conditions, especially the spectrum of dermatitides. Ballooning is intracellular edema characteristic of virally infected cells.

II. A small bulla is arbitrarily called a vesicle.

Vesicles and bullae may arise from primary cell damage or acantholysis. They may be located under the keratin layer (subcorneal), between the epithelium and dermis (junctional), or in the middle layers of epithelium.

Atrophy

I. Atrophy (see subsection Atrophy later, under Aging, and Fig. 6.8) is (1) thinning of the epidermis; (2) smoothing or diminution (effacement) of rete ridges (“pegs”); (3) disorder of epidermal architecture; (4) diminution or loss of epidermal appendages such as hair; and (5) alterations of the collagen and elastic dermal fibers.

II. Atrophy is commonly seen in aging. It may also be seen in the epidermis overlying a slow-growing tumor in the corium.

Atypical Cell

I. An atypical cell (see Fig. 6.4B) is one in which the normal nucleus-to-cytoplasm ratio is altered in favor of the nucleus, which stains darker than normal (hyperchromasia), may show an abnormal configuration (giant form or multinucleated form), may have an abnormal nuclear configuration (e.g., indented, cerebriform, multinucleated), or may contain an abnormal mitotic figure (e.g., tripolar metaphase). If sufficiently atypical, according to generally accepted criteria, the cell may be classified as cancerous.

It is the overall pattern of the tissue rather than any one individual cell that aids in the diagnosis of cancer; one dyskeratotic or atypical cell does not necessarily mean the tissue is cancerous.

II. Isolated atypical cells may be found in benign conditions such as actinic keratosis and pseudoepitheliomatous hyperplasia. Atypical cells may be abundant in malignant conditions such as carcinoma in situ and squamous cell carcinoma.

Congenital Abnormalities

Dermoid and Epidermoid Cysts

See Chapter 14.

Phakomatous Choristoma

I. Phakomatous choristoma (Fig. 6.6) is a rare, congenital, choristomatous tumor (i.e., a tumor of tissue not normally found in the area) of lenticular anlage, usually involving the inner aspect of the lower lid.

II. Histologically, cells resembling lens epithelial cells and lens “bladder” cells along with patches of a thick, irregular periodic acid–Schiff (PAS)-positive membrane closely simulating lens capsule are seen growing irregularly in a dense fibrous tissue matrix.

Positive staining for vimentin, S-100 protein, and numerous antibodies against lens-specific proteins strongly supports the lenticular anlage origin.

Positive staining for vimentin, S-100 protein, and numerous antibodies against lens-specific proteins strongly support the lenticular anlage origin. An unusual complex choristoma of the lateral canthus has been reported to contain elements of hair follicle nevus, bulbar dermoid, epibulbar osseous choristoma, and accessory tragus.

Miscellaneous Choristomas and Hamartomas

I. Nevus lipomatosus (pedunculated nevus) is a gradually enlarging congenital eyelid papule. Histologically, the lesion is polypoid in shape and consists of mature adipocytes within the dermis and subconjunctival mucosa consistent with nevus lipomatosus.

II. Juvenile hyaline fibromatosis is characterized by multiple facial nodules, gingival fibromatosis, and osteolytic lesions in the proximal metaphysis of the tibia and humerus symmetrically. It may present as an eyelid tumor scalloping the superior orbital osseous rim and resulting in blepharoptosis.

III. Neurocutaneous pattern syndromes are a group of disorders characterized by congenital abnormalities involving both the skin and the nervous system for which no identifiable cause has been isolated. Examples are encephalocraniocutaneous lipomatosis, oculocerebrocutaneous syndrome, and linear nevus sebaceous syndrome.

A. Encephalocraniocutaneous lipomatosis is rare and characterized by congenital cutaneous, ocular, and neurologic abnormalities, particularly involving the head and neck.

It has been reported in a boy with lipomatous brown pigmented plaques of the top of the skull with accompanying alopecia, ptosis, bulbar conjunctival lipodermoid, microcalcifications, and atrophy of the cerebral parenchyma, and widening of the frontal subarachnoid space and the fissure of Sylvius. There were accompanying intraoral lesions, maxillary compound odontoma, and juvenile extranasopharyngeal angiofibroma of the gingiva.

B. Congenital lipoblastoma of the scalp and eyelid is very rare. Histopathologic examination shows lobular adipose tissue separated by fibrous septa.

IV. Caliber persistent artery refers to a large-caliber artery that is present adjacent to an epithelial or mucosal surface.

A. On the head and neck, the lesion most commonly is found on the lower lip, but it has been documented on the eyelid.

B. It is of significance because of the possibility of confusion with a subcutaneous mass lesion and because of its propensity to bleed profusely on attempted biopsy.

C. Histopathologic examination demonstrates a large-caliber artery within the dermis extending at almost right angles to the skin surface.

Cryptophthalmos (Ablepharon)

Microblepharon

Microblepharon is a rare condition in which the lids are usually normally formed but shortened; the shortening results in incomplete lid closure.

Coloboma

I. A coloboma of the lid is a defect that ranges from simple notching at the lid margin to complete absence of a segment of lid.

II. Other ocular and systemic anomalies may be found (see discussion of Goldenhar’s syndrome in Chapter 8).

Eyelid colobomas may be seen in the amniotic deformity, adhesion, and mutilation (ADAM) sequence in which a broad spectrum of anomalies having intrinsic causes (germ plasm defect, vascular disruption, and disturbance of threshold boundaries of morphogens during early gastrulation) alternate with extrinsic causes (amniotic band rupture) to explain the condition. In addition to mutilation (reduction) and deformity (ring constriction) of distal extremities, there can be acrania, cephalocele, typical or atypical facial clefts, and celosomia in addition to skin evidence of a constriction band.

Ectopic Caruncle

A clinically and histologically normal caruncle may be present in the tarsal area of the lower lid.

Eyelash Anomalies

I. Hypotrichosis (madarosis)

A. Primary hypotrichosis (underdevelopment of the lashes) is rare.

Schopf–Schulz–Passarage syndrome is a rare ectodermal dysplasia characterized by hypodontia, hypotrichosis, nail dystrophy, palmoplantar keratoderma, and periocular and eyelid margin hidrocystomas. Multiple palmoplantar eccrine syringofibroadenomas have also been associated with the syndrome.

B. Most cases are secondary to chronic blepharitis or any condition that causes lid margin scarring or lid neoplasms—for example, sebaceous gland carcinoma.

C. Secondary eyelash loss may be associated with hyperthyroidism.

II. Hypertrichosis is an increase in length or number of lashes.

A. Trichomegaly is an increase in the length of the lashes.

Increased eyelash length may be associated with allergic diseases.

B. Polytrichia is an increase in the number of lashes: (1) distichiasis—two rows of cilia; (2) tristichiasis—three rows of cilia; and (3) tetrastichiasis—four rows of cilia.

Distichiasis is the term used for the congenital presence of an extra row of lashes, whereas trichiasis is the term used for the acquired condition, which is usually secondary to lid scarring. Distichiasis may be associated with late-onset hereditary lymphedema (see section on Congenital Conjunctival Lymphedema in Chapter 7). The syndrome is characterized by lymphedema of the limbs, with variable age of onset, and extra aberrant growth of eyelashes from the meibomian glands. Mutation of the FOXC2 gene (a member of the forkhead/winged family of transcription factors) has been associated with the lymphedema–distichiasis syndrome. It has been postulated that hereditary distichiasis and lymphedema–distichiasis may not be separate genetic disorders but, rather, different phenotypic expressions of the same underlying disorder. Continue small print. A form of congenital hypertrichosis in the periorbital region, associated with cutaneous hyperpigmentation, may overlie a neurofibroma.

III. Ectopic cilia

A. Ectopic cilia is a rare choristomatous anomaly in which a cluster of lashes grows in a location (lid or conjunctiva) remote from the eyelid margin.

B. A case of complex eyelid choristoma containing ectopic cilia and a functioning lacrimal gland has been reported.

Ichthyosis Congenita

I. Ichthyosis (Fig. 6.7) can be divided into four types:

A. Autosomal-dominant ichthyosis vulgaris (onset usually in first year of life)

B. Autosomal-dominant ichthyosis congenita (ichthyosiform erythroderma, onset at birth), with a generalized bullous form and a localized nonbullous form (ichthyosis hystrix)

C. X-linked recessive ichthyosis vulgaris [the rarest type (Xp22.32), onset at 1–3 weeks]

D. Autosomal-recessive ichthyosis congenita with a severe harlequin type and a less severe lamellar type (onset at birth)

1. Keratinocyte transglutaminase (TGK) activity mediates the cross-linkage during the formation of the normal cornified cell membrane.

2. Intact cross-linkage of cornified cell envelopes is required for epidermal tissue homeostasis.

3. In lamellar ichthyosis, TGK levels are drastically reduced, causing the keratinocytic defect in the disease.

II. All types have in common dryness of the skin with variable amounts of profuse scaling.

Only in the autosomal-recessive type do ectropion of the lids and conjunctival changes develop.

III. Cicatricial ectropion is a common finding in recessive ichthyosis congenita.

A. Corneal changes such as gray stromal opacities (dystrophica punctiformis profunda) occur in ichthyosis vulgaris and autosomal-recessive ichthyosis congenita.

In X-linked ichthyosis, corneal changes may occur that electron microscopically resemble the changes in lecithin cholesterol acyltransferase disease.

B. Superficial corneal changes (punctate epithelial erosions, gray elevated nodules, and band-shaped keratopathy) also occur.

IV. The differential diagnosis includes ectodermal dysplasia, poikiloderma congenitale (Rothmund–Thomson syndrome), adult progeria (Werner’s syndrome), keratosis palmaris et plantaris, keratosis follicularis spinulosa decalvans (Siemens’ disease), epidermolysis bullosa, and the syndrome of ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome, a rare neuroichthyosis that is probably X-linked recessive).

Keratitis–ichthyosis–deafness (KID) syndrome is a rare congenital ectodermal dysplasia characterized by the presence of hyperkeratotic skin lesions, moderate to profound sensorineural hearing loss, and vascularizing keratitis. Genetic mutations in the GJB2 gene coding for connexin 26, which is a component of gap junctions in epithelial cells, have been detected in the disorder. Specific associated ocular and adnexal findings are lid abnormalities, corneal surface instability, limbal stem cell deficiency with resulting corneal complications, and dry eye.

V. Histologically, the epidermis is thickened and covered by a thick, dense, orthokeratotic scale.

In the autosomal-recessive type, the conjunctiva may show a papillary reaction with hyperkeratosis and parakeratosis of the epithelium.

Aging

Atrophy

See subsection Atrophy, earlier, under Terminology.

Dermatochalasis

I. Dermatochalasis (Fig. 6.8) is an aging change characterized by lax, redundant skin of the lids. The folds may cover the palpebral fissure, even impairing vision.

Dermatochalasis should not be confused with blepharochalasis, an uncommon condition characterized by permanent changes in the eyelids after recurrent and unpredictable attacks of edema, usually in people younger than 20 years of age. Elastin mRNA expression in cultured fibroblasts from blepharochalasis is not decreased, suggesting that environmental factors or other matrix components of elastic fibers may be involved in the loss of elastic fibers found in the disorder. Also, the Melkersson–Rosenthal syndrome (triad of recurrent labial edema, relapsing facial paralysis, and fissured tongue) can present with eyelid edema of “unknown cause.”

II. Histologically, the epidermis appears thin and smooth with decreased or absent rete ridges.

In the corium, some loss of elastic and collagen tissue occurs along with an increase in capillary vascularity, an often basophilic degeneration of the collagen (actinic elastosis), and a mild lymphocytic inflammatory reaction.

Inflammation

Terminology

I. Dermatitis (synonymous with eczema, eczematous dermatitis)

A. Dermatitis is a diffuse inflammation of the skin caused by a variety of cutaneous disorders, some quite specific and others nonspecific.

B. It may be acute (erythema and edema progressing to vesiculation and oozing, then to crusting and scaling), subacute (intermediate between acute and chronic), or chronic (papules, plaques with indistinct borders, less intense erythema, increased skin markings—lichenification—containing fine scales and firm or indurated to palpation).

II. Blepharitis (dermatitis of the lids is called blepharitis)

A. Blepharitis is a simple diffuse inflammation of the lids.

A granulomatous blepharitis, which is part of Melkersson–Rosenthal syndrome (triad of recurrent labial edema, relapsing facial paralysis, and fissured tongue), may present along with lid edema.

B. Seborrheic blepharitis refers to a specific type of chronic blepharitis primarily involving the lid margins and often associated with dandruff and greasy scaling of the scalp, eyebrows, central face, chest, and pubic areas.

1. Red, inflamed lid margins and yellow, greasy scales on the lashes are characteristic.

2. Histologically, the epidermis shows spongiosis, a mild, superficial perivascular, predominantly lymphohistiocytic, mononuclear cell infiltrate in the superficial dermis, and even acanthosis, orthokeratosis, or parakeratosis, alone or in combination.

C. Blepharoconjunctivitis refers to a specific type of chronic blepharitis involving the lid margins primarily and the conjunctiva secondarily.

1. Sensitivity to Staphylococcus is the likely cause.

2. The chronic inflammation may result in loss (madarosis) or abnormalities (e.g., trichiasis) of the eyelashes along with secondary phenomena such as hordeolum and chalazion. The lid margins may be thickened and ulcerated with gray, tenacious scales at the base of the remaining lashes.

3. Histologically, a vascularized, chronic, nongranulomatous inflammation, often containing neutrophils, is associated with acanthosis, orthokeratosis, or parakeratosis of the epidermis.

D. Cellulitis refers to a specific type of acute, infectious blepharitis primarily involving the subepithelial tissues.

1. Histologically, polymorphonuclear leukocytes, vascular congestion, and edema predominate.

2. Bacteria, especially Streptococcus, are the usual cause.

Erysipelas is a specific type of acute cellulitis caused by group A hemolytic streptococci that is characterized by a sharply demarcated, red, warm, dermal and subcutaneous facial plaque.

III. Hordeolum (Fig. 6.9)

A. An external hordeolum (stye) results from an acute purulent inflammation of the superficial glands (sweat and sebaceous) and hair follicles of the eyelids.

1. It presents clinically as a discrete, superficial, elevated, erythematous, warm, tender papule or pustule, usually on or near the lid margin.

2. Histologically, polymorphonuclear leukocytes, edema, and vascular congestion are centered primarily around hair follicles and adjacent structures.

B. An internal hordeolum, presenting clinically as a diffuse, deep, tender, warm erythematous area involving most of the lid, results from an acute purulent inflammation of the meibomian glands in the tarsal plate of the eyelids.

Hordeolum can be considered simply as an inflammatory papule or pustule (pimple) of the lid. An external hordeolum is located superficially; an internal hordeolum is deep and points internally.

IV. Chalazion (Fig. 6.10)

A. Chronic inflammation of the meibomian glands (deep chalazion) or Zeis sebaceous glands (superficial chalazion) results in a hard, painless nodule in the eyelid called a chalazion or lipogranuloma of the lid. A chalazion may result from an internal hordeolum or may start de novo.

A lipogranuloma is composed of an extracellular accumulation of fat, as opposed to a xanthoma, which consists of an intracellular accumulation of fat.

B. If the chalazion ruptures through the tarsal conjunctiva, granulation tissue growth (fibroblasts, young capillaries, lymphocytes, and plasma cells) may result in a rapidly enlarging, painless, polypoid mass (granuloma pyogenicum; Fig. 6.11).

C. Histologically, a zonal lipogranulomatous inflammation is centered around clear spaces previously filled with lipid but dissolved out during tissue processing.

1. Polymorphonuclear leukocytes, plasma cells, and lymphocytes may also be found in abundance.

2. Not infrequently, multinucleated giant cells (resembling foreign-body giant cells or Langhans’ giant cells) and even asteroid and Schaumann’s bodies—all nonspecific findings—may be seen.

Recurrent giant chalazia may be found in the hyperimmunoglobulin E (Job) syndrome. The syndrome is a rare immunodeficiency and multisystem disorder characterized by recurrent skin and pulmonary abscesses, connective tissue abnormalities, and elevated levels of serum immunoglobulin E (IgE).

V. Acne rosacea

A. Acne rosacea affects mainly the skin of the middle face, nose, cheeks, forehead, and chin, and it presents in three types, which may occur separately or together: (1) an erythematous telangiectatic type with erythema, telangiectasis, follicular pustules, and occasional abscesses; (2) a glandular hyperplastic type with enlargement of the nose (rhinophyma); and (3) a papular type with numerous, moderately firm, slightly raised papules 1 to 2 mm in diameter and associated with diffuse erythema.

Many dermatologists believe that some cases of acne rosacea are caused by large numbers of Demodex (see subsection Demodicosis, later).

B. Ocular involvement is commonly found and consists of blepharitis, chalazion, conjunctival and lid granulomas, episcleritis, hyperemic conjunctivitis, internal hordeolum, keratitis, lid margin telangiectasis, meibomianitis, squamous metaplasia of the meibomian duct, and superficial punctate keratopathy.

C. Histology

1. Type 1 shows dilated blood vessels and a nonspecific, dermal, chronic nongranulomatous inflammatory infiltrate often associated with pustules (i.e., intrafollicular accumulations of neutrophils).

2. Type 2 shows hyperplasia of sebaceous glands along with the findings seen in type 1.

3. Type 3 shows papules composed of either a chronic nongranulomatous inflammatory infiltrate or, frequently, a granulomatous inflammatory infiltrate simulating tuberculosis (formerly called rosacea-like, tuberculid, or lupoid rosacea).

VI. Relapsing febrile nodular nonsuppurative panniculitis (Weber–Christian disease)—see later in this chapter.

Viral Diseases

I. Molluscum contagiosum (Fig. 6.12)

A. Clinically, a dome-shaped, small (1–3 mm), discrete, waxy papule, often multiple, is seen with a characteristic umbilicated center (central dell).

Blepharoconjunctivitis associated with molluscum contagiosum may occur in the Wiskott–Aldrich syndrome (WAS), which is characterized by atopic dermatitis, thrombocytopenic purpura, normal-appearing megakaryocytes but small, defective platelets, and increased susceptibility to infections. The syndrome represents an immunologically deficient state (decreased levels of serum IgM and increased levels of IgA and IgE) and is transmitted as an X-linked recessive trait (abnormal gene on Xp11–11.3 chromosome). WASp, the protein made by the gene that is defective in WAS, is impaired. Another condition, acquired immunodeficiency syndrome (AIDS; see Chapter 1), may show multiple eyelid lesions of molluscum or present initially with molluscum eyelid lesions. In addition, multiple epibulbar molluscum lesions have been reported in association with atopic dermatitis.

B. The large pox virus replicates in the cytoplasm and is seen histologically as large, homogeneous, purple, intracytoplasmic inclusion bodies (molluscum bodies) in a markedly acanthotic epidermis.

1. In the deeper layers of the epidermis, near the basal layer, viruses are present as tiny, eosinophilic, intracytoplasmic inclusions. As the bodies extend toward the surface, they grow so enormous that they exceed the size of the invaded cells.

2. At the level of the epidermal granular layer, the large bodies change from eosinophilic to basophilic.

II. Verruca (wart; Fig. 6.13)

A. Verruca vulgaris (anywhere on the skin), verruca plana (mainly on face and dorsa of hands), verruca plantaris (soles of feet), and condyloma acuminatum (glans penis, mucosa of female genitalia, and around anus) are all caused by a variety of the papillomaviruses.

B. Verruca vulgaris appears as a small papule containing a digitated surface or an elongated, filiform wart around the eyelids, usually at or near the lid margin.

C. Histologically, massive papillomatosis, marked by acanthosis, parakeratosis, and orthokeratosis and containing collections of serum in the stratum corneum at the tips of the digitations, is seen.

1. Characteristically, in early lesions, cells in the upper part of the squamous layer and in the granular layer are vacuolated.

2. The vacuolated keratocytes contain condensation and clumping of dark-staining keratohyaline granules and occasional intranuclear eosinophilic inclusion bodies, which represent virus inclusions.

III. Viral vesicular lesions

A. Infections with the viruses of variola (smallpox), vaccinia (cowpox), varicella (chickenpox), herpes zoster (shingles), and primary and recurrent herpes simplex all produce similar erythematous–vesicular–pustular and crusted papular eruptions.

B. Histologically, an intraepidermal vesicle characterizes all five diseases (see Fig. 6.5).

1. Marked interepidermal spongiosis involves the deep epidermis and results in swollen epidermal cells that lose their intercellular bridges, causing acantholysis and intraepidermal vesicle formation.

2. Reticular degeneration and necrosis and massive ballooning degeneration involve the superficial and peripheral epidermis and result in enormous swelling of the squamous cells (intracellular edema), causing them to burst so that only the resistant parts of cell walls remain as septa forming a multilocular vesicle.

Ballooning degeneration is specific for viral vesicles, whereas reticular degeneration is seen in acute dermatitis (e.g., poison ivy).

3. Multinucleated epithelial giant cells, often with steel-gray nuclei showing peripheral margination of clumped chromatin, may be seen with herpes simplex and herpes zoster.

4. A dense, superficial, dermal, perivascular lymphohistiocytic inflammation, often with neutrophils infiltrating the epidermis, is seen.

5. Eosinophilic inclusion bodies are found in all five diseases, mainly in the cytoplasm in variola and in vaccinia (Guarnieri bodies). They are occasionally found in the nucleus in variola, but exclusively in the nucleus (usually surrounded by a halo or clear zone) in varicella, herpes zoster, and herpes simplex.

IV. Trachoma and lymphogranuloma venereum (see Chapter 7).

Fungal and Parasitic Diseases

See subsections on fungal and parasitic nontraumatic infections in Chapter 4.

I. Demodicosis (Fig. 6.14)

A. The parasitic mite, Demodex folliculorum, lives in the hair follicles in humans and certain other mammals, especially around the nose and eyelashes. Demodex brevis lives in eyelash and small hair sebaceous glands, and in lobules of meibomian glands.

B. Although present in almost all middle-aged and elderly people, and in a significant percentage of younger people, the mites seem relatively innocuous and only rarely produce any symptoms.

Many dermatologists believe that some cases of acne rosacea and folliculitis are caused by large numbers of Demodex, especially in immunosuppressed patients.

C. Histologically, the mite is often seen as an incidental finding in a hair follicle in skin sections.

D. No inflammatory reaction is associated with the mite.

II. Phthirus pubis (Fig. 6.15)

A. Infestation of the eyelashes and brow by P. pubis, the crab louse, is called phthiriasis palpebrarum.

B. Transmission from the primary site of infestation, the pubic hair, is usually by hand.

1. The louse, or several lice, grips the bottom of the lash with its claw.

2. The ova (nits) are often present in considerable numbers, adhering to the lashes.

3. A secondary blepharoconjunctivitis may be present.

Lid Manifestations of Systemic Dermatoses or Disease

Ichthyosis Congenita

See section Congenital Abnormalities earlier in this chapter.

Xeroderma Pigmentosum

See section Congenital Abnormalities earlier in this chapter.

Pemphigus

See Chapter 7.

Ocular involvement in pemphigus vulgaris occurs rarely and is usually limited to the conjunctiva and/or the eyelids. In contrast, pemphigus foliaceus involves the skin of the eyelid and not the conjunctiva.

Ehlers–Danlos Syndrome (“India-Rubber Man”)

I. Ehlers–Danlos (ED) syndrome consists of a rare, heterogeneous group of disorders characterized by loose-jointedness, hyperextensibility, fragile skin with “cigarette paper” scarring, generalized friability of tissues, vascular abnormalities with rupture of great vessels, hernias, gastrointestinal diverticula, and friability of the bowel and lungs.

Most cases are inherited as autosomal-dominant traits, and the others show an X-linked recessive or autosomal-recessive pattern (including one probably distinct “ocular” form; i.e., type VI). The skin in ED syndrome is hyperextensible but not lax. When it is pulled, it stretches; when let go, it quickly springs to the original position. The skin in cutis laxa (see subsection Cutis Laxa, later), on the other hand, tends to return slowly after it is pulled.

II. The basic problem appears to be an abnormal organization of collagen bundles into an intermeshing network, interfering with cross-linking.

Most patients with ED syndrome type VI (ocular type) lack lysyl hydroxylase, an enzyme that catalyzes the hydroxylation of lysine to hydroxylysine. In hydroxylysine deficiency, the structural integrity of collagen is thought to be diminished because hydroxylysine is an important source of cross-links in collagen. A few cases of ED syndrome type VI, however, show normal activity of the enzyme lysyl hydroxylase. Therefore, two variants of ED syndrome type VI may exist.

III. Ocular findings include epicanthus (the most common finding), hypertelorism, poliosis, strabismus, blue sclera, microcornea, megalocornea, myopia, keratoconus, ectopia lentis, intraocular hemorrhage, neural retinal abnormalities, and angioid streaks.

IV. Histologically, conjunctival biopsies studied by light and electron microscopy showed no abnormalities. The pathologic lesions in ED syndrome are controversial.

Pseudoxanthoma Elasticum

I. Pseudoxanthoma elasticum is mostly inherited in an autosomal-recessive manner, but also in an autosomal-dominant pattern. It mainly involves the skin, the eyes, and the cardiovascular system.

Linkage analysis and mutation detection techniques have shown mutations in the ABCC6 gene.

A. The skin of the face, neck, axillary folds, cubital areas, inguinal folds, and periumbilical area (often with an umbilical hernia) becomes thickened and grooved, with the areas between the grooves diamond-shaped, rectangular, polygonal, elevated, and yellowish (resembling chicken skin).

1. The skin in the involved areas becomes lax, redundant, and relatively inelastic.

2. The skin changes may not be noted until the second decade of life or later.

B. The eyes show angioid streaks (see Fig. 11.38), sometimes with subretinal neovascularization.

1. Examination of the fundus may show a background pattern, called peau d’orange, in the posterior aspect of the eyes, caused by multiple breaks in Bruch’s membrane.

2. The optic nerve may contain drusen.

Drusen of the optic nerve occurs 20–50 times more often in pseudoxanthoma elasticum than in the general, healthy population.

C. The cardiovascular system manifestations include weak or absent peripheral pulses, intermittent claudication, angina pectoris, and internal hemorrhages.

II. The basic defect seems to be related to a dystrophy of elastic fibers, but some think collagen fibers are at fault.

III. Histologically, the skin shows elastin abnormalities only in the midepidermis, with elastin band swelling, granular degeneration, and fragmentation. Angioid streaks consist of breaks in Bruch’s membrane.

Toxic Epidermal Necrolysis

I. Toxic epidermal necrolysis (Lyell’s disease; epidermolysis necroticans combustiformis; acute epidermal necrolysis; scalded-skin syndrome) really consists of two different diseases, Lyell’s disease (subepidermal type or true toxic epidermal necrolysis—probably a variant of severe erythema multiforme) and Ritter’s disease (subcorneal type or staphylococcal scalded-skin syndrome—not related to toxic epidermal necrolysis).

A. Toxic epidermal necrolysis (Lyell’s disease) is probably a variant of severe erythema multiforme, frequently occurs as a drug allergy, often overlaps with Stevens–Johnson syndrome, and histologically resembles the epidermal type of erythema multiforme.

B. Staphylococcal scalded-skin syndrome (Ritter’s disease) is not related to erythema multiforme, occurs largely in the newborn and in children younger than five years, and occurs as an acute disease.

1. Its onset begins abruptly with diffuse erythema accompanied by severe malaise and high fever.

2. Large areas of epidermis form clear fluid-filled, flaccid bullae, which exfoliate almost immediately so that the denuded areas resemble scalded skin.

Phage group II staphylococci are absent from the bullae but are present at a distant site (e.g., purulent conjunctivitis, rhinitis, or pharyngitis). The bullae are caused by a staphylococcal toxin called exfoliatin.

3. The disease runs an acute course and is fatal in fewer than 4% of cases.

It rarely occurs in adults, but when it does, it may have a mortality rate of greater than 50%.

II. Histologically, most cases of toxic epidermal necrolysis show a severe degeneration and necrosis of epidermal cells resulting in detachment of the entire epidermis (flaccid bullae).

Contact Dermatitis

I. An allergenic or irritating substance applied to the skin may result in contact dermatitis, which is a type IV immunologic reaction requiring a primary exposure, sensitization, and re-exposure to an allergen, and then an immunologic delay before clinical expression of the dermatitis.

A. Contact dermatitis is one of the most common abnormal conditions affecting the lids.

B. Agents such as cosmetics and locally applied atropine and epinephrine may produce a contact dermatitis.

C. Contact dermatitis may be present in three forms:

1. An acute form with diffuse erythema, edema, oozing, vesicles, bullae, and crusting

2. A chronic form with erythema, scaling, and thick, hard, leathery skin (lichenification)

3. A subacute form showing characteristics of acute and chronic forms

Anterior subcapsular cataracts (usual form) and posterior subcapsular cataracts (rare form) seem to occur with increased frequency in patients who have a history of atopia.

II. Histology

A. In the acute stage, epidermal (intraepidermal vesicles) and dermal edema predominate along with a lymphocytic infiltrate.

Spongiosis or intercellular edema between squamous cells contributes to the formation of vesicles (unilocular bullae). Intracellular edema, however, results in reticular degeneration and the formation of multilocular bullae.

B. In the chronic stage, there is acanthosis, orthokeratosis, and some parakeratosis together with elongation of rete pegs.

1. Mild spongiosis is present, but vesicle formation does not occur.

2. In the dermis, perivascular lymphocytes, eosinophils, histiocytes, and fibroblasts are found.

Histologically, a distinction cannot be made between a primary allergic contact dermatitis and an irritant-induced or toxic dermatitis, except possibly in the early stage. Atopic dermatitis, which is a chronic, severely pruritic dermatitis associated with a personal or family history of atopy, does not show vesicles, although it does show lichenified and scaling erythematous areas, which when active may show oozing and crusting.

Collagen Diseases

I. Dermatomyositis (see Chapter 14)

II. Periarteritis (polyarteritis) nodosa

A. Periarteritis nodosa is characterized by a panarteritis of small and medium-sized, muscular-type arteries of kidney, muscle, heart, gastrointestinal tract, and pancreas, but not of the central nervous system or lungs, and rarely of the skin.

A benign cutaneous form of periarteritis nodosa exists as a chronic disease limited to the skin and subcutaneous tissue.

B. Histologically, four stages may be seen:

1. The degenerative or necrotic stage: Foci of necrosis (fibrinoid necrosis) involve the coats of the artery and may result in localized dehiscences or aneurysms.

2. The inflammatory stage: Inflammatory cells, predominantly neutrophils but also eosinophils and lymphocytes, infiltrate the necrotic areas.

3. The granulation stage: Healing occurs with the formation of granulation tissue, which may occlude the vascular lumens.

4. The fibrotic stage: Healing ends with scar formation.

III. Lupus erythematosus can be subdivided into three types:

1. Chronic discoid, which is limited to the skin

a. Discoid lupus erythematosus involving the eyelids is rare. It may present as madarosis.

b. Periorbital edema and erythema are rare cutaneous manifestations of discoid lupus erythematosus.

2. Intermediate or subacute, which has systemic symptoms in addition to skin lesions

3. Systemic, which is dominated by visceral lesions

Transition from the chronic discoid type to the systemic type occurs infrequently.

A. Histology shows five (all five not necessarily present in each case) main characteristics when they involve the skin. The three types of lupus erythematosus differ only in degree of involvement (the systemic form is the most severe): (1) orthokeratosis with keratotic plugging found mainly in the follicular openings but also found elsewhere; (2) atrophy of the squamous layer of epidermis and of rete pegs; (3) liquefaction degeneration of basal cells (i.e., vacuolation and dissolution of basal cells—most significant finding); (4) focal lymphocytic dermal infiltrates mainly around dermal appendages; and (5) edema, vasodilatation, and extravasation of erythrocytes in the upper dermis.

IV. Scleroderma (Fig. 6.17) exists in two forms: (1) a benign circumscribed (morphea) form, which almost never progresses or transforms to the systemic form, and (2) a systemic form (progressive systemic sclerosis), which may prove fatal.

A. The characteristic lesion is a sclerotic plaque with an ivory-colored center and appearing bound-down when palpated.

B. Ocular findings include pseudoptosis secondary to swollen lids, hyposecretion of tears with trophic changes in the cornea and conjunctiva (Sjögren’s syndrome), ocular muscle palsies, temporal arteritis, unilateral glaucoma, exophthalmos, neural retinal cotton-wool patches, signs of hypertensive retinopathy, defects of the retinal pigment epithelium near the macula, central serous choroidopathy, and fluorescein leaks of thickened retinal capillaries.

C. Histologically, the morphea and the systemic forms are similar, if not identical.

1. Early stage: Dermal collagen bundles appear swollen and homogeneous and are separated by edema. Round inflammatory cells, mainly lymphocytes, are found around edematous blood vessel walls and between collagen bundles (panniculitis).

2. Intermediate stage: Subcutaneous tissue is infiltrated by round inflammatory cells, dermal collagen becomes further thickened, and dermal adnexa are involved in the process. Blood vessel walls show edema with intimal proliferation and narrowing of their lumina.

3. Late stage: Dermis is thickened by the addition of new collagen at the expense of subcutaneous tissue. Inflammation is minor or absent.

a. The subcutaneous fat is replaced by collagen, and blood vessels are fibrotic.

b. The thickened dermis contains hyalinized, hypertrophic, closely packed collagen bundles; atrophic sweat glands trapped in the midst of collagen bundles; decreased fibrocytes; and few or no sebaceous glands or hair structures.

4. The overlying epidermal structure, including rete ridges, is rather well preserved except in the late stages of the systemic form, when atrophy occurs.

5. The underlying muscle, especially in the systemic form, may be involved and shows early degeneration, swelling, and inflammation, followed by late fibrosis.

Granulomatous Vasculitis

I. Wegener’s granulomatosis

A. Classic form: characterized by generalized small-vessel vasculitis, necrotizing granulomas, focal necrotizing glomerulonephritis, and vasculitis of the upper and lower respiratory tract.

1. Typical presentation is a persistent inflammatory nasal and sinus disease associated with systemic symptoms of fever, malaise, and migratory arthritis.

2. Serum antineutrophilic cytoplasmic antibodies (ANCAs) are a sensitive and rather specific marker for Wegener’s granulomatosis.

3. A limited form of Wegener’s granulomatosis lacks renal involvement (see Fig. 8.64).

4. In both classic and limited forms, most of the ocular findings can occur.

5. Ocular involvement, most commonly orbital, occurs in up to 50% and neurologic involvement in up to 54% of cases.

B. Ocular findings include dry eyes, nasolacrimal obstruction, blepharitis, conjunctivitis, scleritis or episcleritis, corneoscleral ulceration, uveitis, retinal vein occlusion, retinal pigmentary changes, acute retinal necrosis, choroidal folds, optic neuritis, and exophthalmos secondary to orbital involvement. It has presented as cicatricial conjunctival inflammation with trichiasis.

C. Histologically, the classic triad of necrotizing vasculitis (granulomatous and disseminated small-vessel), tissue necrosis, and granulomatous inflammation are characteristic. The vasculitis can be seen in three forms:

1. Microvasculitis or capillaritis—infiltration and destruction of capillaries, venules, and arterioles by neutrophils

2. Granulomatous vasculitis (most characteristic)—granulomatous vasculitis involving small or medium-sized arteries and veins

3. Necrotizing vasculitis involving small or medium-sized arteries and veins but not associated with granulomatous inflammation

II. Allergic granulomatosis (allergic vasculitis, Churg–Strauss syndrome) involves the same-size arteries as periarteritis but differs in having respiratory symptoms, pulmonary infiltrates, systemic and local eosinophilia, intravascular and extravascular granulomatous lesions, and often cutaneous and subcutaneous nodules and petechial lesions.

III. Temporal arteritis (see Chapter 13)

Vasculitis-Like Disorders and Leukemia/Lymphoma

I. Natural killer (NK) T-cell lymphoma (polymorphic reticulosis or angiocentric T-cell lymphoma)

A. NK cells are a distinct non-T, non-B lineage of lymphocytes that mediate major histocompatibility complex-unrestricted cytotoxicity.

B. NK/T-cell malignancies are uncommon and were previously known as polymorphic reticulosis or angiocentric T-cell lymphomas. The World Health Organization further divides these lesions into NK/T-cell lymphoma (nasal and extranasal) type and aggressive NK-cell leukemia.

1. Its lymphoma cells are CD2+, CD56+, and CD3ε+.

C. Relatively common in Asia, Mexico, and South America, but extremely rare in most Western countries.

D. Lethal midline granuloma form of NK/T-cell lymphoma is a rare entity, usually arises in the nasal cavity, has a male preponderance and a wide age range, is extremely aggressive, and has approximately a 20% five-year survival.

E. Apoptosis, necrosis, and angioinvasion are typical features of the lymphoma.

F. Invasion and blockage of blood vessels by lymphoma cells result in marked ischemic necrosis of normal and neoplastic tissues.

G. The leukemic form tends to affect younger patients, who often present with advanced disease and multiple organ involvement. Survival is particularly brief.

H. γδ T-cell receptor clonality is the most common T-cell receptor rearrangement in several T-cell lymphomas, including NK/T-cell lymphoma.

I. Characteristic patterns of genomic alteration typify aggressive NK-cell leukemia and extranodal NK/T-cell lymphoma, nasal type.

J. Epstein–Barr virus (EBV) can encode multiple genes that drive cell proliferation and confer resistance to cell death, including two viral proteins that mimic the effects of activated cellular signaling proteins.

1. Infection with the virus is associated with a variety of lymphomas and lymphoproliferative disorders, including Burkitt’s lymphoma; NK/T-cell lymphoma, lymphoma and lymphoproliferative diseases in immunocompromised individuals, and Hodgkin’s lymphoma.

2. The presence of EBV-infected cells in the aqueous humor originating from nasal NK/T-cell lymphoma has been reported.

K. The majority of ocular adnexal lymphomas are marginal zone B-cell (mucosal-associated lymphoid tissue: MALT) lymphomas.

L. NK/T-cell lymphoma has occasionally involved the eye.

II. CD30+ lymphoid proliferations (Table 6.1)

A. Include lymphoid papulosis, primary cutaneous anaplastic large cell lymphoma, and systemic anaplastic large cell lymphoma.

B. 30% of all cutaneous T-cell lymphomas.

C. Spectrum of clinical aggressiveness.

D. Proper diagnosis requires clinical and pathologic correlation.

TABLE 6.1

Clinical and Pathologic Findings in CD30+ Lymphoid Proliferations

LyP cALCL Systemic ALCL
Demographics

Median age: 45 years

Median age: 60 years

Males <30 years
Symptoms/clinical findings

• Recurrent papular/nodular lesions on trunk/extremities ± ulceration with spontaneous regression after 4–6 weeks.

• Hyper- or hypopigmented scar may remain.

• ≥1 lesion that is >2 cm in diameter ± erythema and ulceration

• No extracutaneous involvement

• Stage III or IV with B symptoms

• Noncontiguous lymphadenopathy

• 40% with extranodal disease
Histology

A: Resembles Hodgkin’s disease with large cells resembling Reed–Sternberg cells

B: Resembles mycosis fungoides with cerebriform cells

C: Resembles ALCL with clusters and sheets of large cells

• Sheets of large cells with irregular nuclei within dermis and subcumneous region

• Epidermis spared

• Large cells with prominent nucleoli in lymph node sinuses and paracortex.

• Multinucleated cells, Reed–Sternberg-like cells, doughnut cells, and hallmark cells may be seen.

• Six histologic variants; neutrophil-rich variant may be mistaken for LyP, type A.
Contrasts in immunohistochemistry

CD30 +

CLA +

EMA –

CD30 +

CLA expression variable

EMA +

CD30 +

CLA expression minimal

EMA +

Bcl-2: Expressed in ALCL > cALCL > LyP

CD56: Expressed in ALCL > cALCL > LyP; poor prognosis in ALCL

Fascin: Expressed in ALCL > cALCL > LyP

TRAF-I: Expressed in LyP ≫ cALCL > ALCL
Treatment

• Usually none.

• PUV A or low-dose MTX has been used for aggressive disease.

• Resection ± irradiation

• Low-dose MTX for skin-restricted disease

• Chemotherapy for extracutaneous disease

• Local radiation with combination chemotherapy
Prognosis

• Benign

• Increased risk for progressing to mycosis fungoides, Hodgkin’s lymphoma, or ALCL

• Less aggressive than systemic ALCL.

• Better survival rate than for systemic ALCL; 5-year survival rate of 90%.

• Spontaneous regression occurs in ≥40%.

• ALK translocation-positive ALCL with better prognosis (5-year survival rate 70–80%) than ALK translocation-negative ALCL (5-year survival rate 30–40%)

image

ALCL, systemic anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; cALCL, primary cutaneous anaplastic large cell lymphoma; CLA, cutaneous lymphocyte antigen; EMA, epithelial membrane antigen: LyP, lymphomatoid papulosis; MTX, methotrexate; PUVA, psoralen plus ultraviolet A; TRAF-I, tumor necrosis factor receptor-associated factor-1.

(From Sanka RK, Eagle RC, Jr., Wojno TH, Neufeld KR, Grossniklaus HE: Spectrum of CD30+ lymphoid proliferations in the eyelid lymphomatoid papulosis, cutaneous anaplastic large cell lymphoma, and anaplastic large cell lymphoma. Ophthalmology 117:343, 2010.)

III. Mycosis fungoides

A. Most common type of cutaneous T-cell lymphoma but rarely involve eyelids.

B. Recalcitrant clinical course.

C. Three classic phases: macular or patch, infiltrative or plaque, and tumor stage.

D. Among the eyelid presentations are ulceration, plaques, facial swelling, and eyelid ectropion.

IV. Other T-cell lymphomas involving the eyelids have been reported.

V. Symmetrical leukemia cutis of the eyelids accompanied by B-cell chronic lymphocytic leukemia has been reported. The differential diagnosis for a cause of such eyelid swelling includes other tumors, hyperthyroidism, nephrotic syndrome, and hypoalbuminemia. In addition, metastasis from the histiocytoid form of breast carcinoma may produce eyelid swelling.

VI. Primary diffuse large B-cell lymphoma has presented as an ulcerating lesion of the eyelid tarsal surface. Positivity of monoclonal antibodies for CD20 and CD79a, and polyclonal antibodies for λ chains, confirmed the diagnosis.

Xanthelasma

I. Xanthelasma (Fig. 6.18) most commonly occurs in middle-aged or elderly people who usually, but not always, have normal serum cholesterol levels.

A. Xanthelasma is a form of xanthoma [i.e., a tumor containing fat mainly within cells (intracellular)], whereas a lipogranuloma (e.g., a chalazion) is a tumor containing fat mainly outside cells (extracellular).

B. It may occur in primary hypercholesterolemia or with nonfamilial serum cholesterol elevation.

Evidence suggests that xanthelasma may be associated with qualitative and quantitative abnormalities of lipid metabolism (increased levels of serum cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B and decreased levels of high-density lipoprotein subfraction 2 cholesterol) that may favor lipid deposition in the skin and arterial wall. Xanthelasma may be a marker of dyslipidemia, and patients who have xanthelasma possibly should undergo a full lipid profile to identify those who are at an increased risk for cardiovascular disease.

C. Xanthelasma is associated with other xanthomas or with hyperlipemia syndromes in approximately 5% of patients.

II. After initial surgical excision, the recurrence rate is probably in the 10 to 20% range.

III. Recurrence is more likely if all four lids are involved, if an underlying hyperlipemia syndrome is present, or if there have been previous recurrences.

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