Skin and Lacrimal Drainage System

6  Skin and Lacrimal Drainage System 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).

SKIN Many of the conditions discussed in this chapter present with eyelid swelling. The more common causes of eyelid swelling are listed in Table 6.1.

NORMAL ANATOMY (Figs. 6.1 and 6.2) Epidermis Lid skin is quite thin. I. The epidermis is composed of a few layers of squamous cells (keratinocytes) and a basal layer; large rete pegs are absent. II. Admixed with the epithelial cells are dendritic melanocytes and Langerhans’ cells (dendritic-appearing cells expressing class II antigen). III. Expression of immunohistochemical markers for cytokeratins, mucin, and stem cells vary considerably among the various epithelia at the mucocutaneous junction of the eyelid. A. At the mucocutaneous junction, CK7, -15 and -19 are absent; however, the epithelium reacts positively for CK1, -4, -8, -10, -13, and -14. B. Reactivity also is found for MUC1 and MUC4, but not for MUC5AC. C. No reactivity is determined for K15, BCRP/ABCG2 and integrin beta1 in the area of the mucocutaneous epithelium, but a strong reactivity is present for N-cadherin.

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).

Acanthosis I. The stratum spinosum (squamous or prickle-cell layer) of the epidermis shows increased thickness (see Fig. 6.3B). II. It is commonly seen in many proliferative epithelial lesions (e.g., papilloma, actinic keratosis, squamous cell carcinomas, and pseudoepitheliomatous hyperplasia).

Dyskeratosis I. Dyskeratosis is keratinization of individual cells within the stratum spinosum, where the cells are not normally keratinized (Fig. 6.4A; see Fig. 7.19). The keratinizing cells show abundant pink (eosinophilic) cytoplasm and small, normalappearing nuclei. In contrast, necrotic keratinocytes have homogeneous pink cytoplasm and nuclear karyolysis and pyknosis.

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

II. Dyskeratosis is characteristic of benign familial intraepithelial dyskeratosis, Darier’s disease, and Bowen’s disease, and is sometimes seen in actinic keratosis, in squamous cell carcinoma, and after sunburn.

Acantholysis I. Acantholysis is a separation of epidermal cells that results from a variety of pathologic processes, and causes a dissolution or degeneration of the intercellular connections (Fig. 6.5). II. Acantholysis is commonly seen in viral vesicles (e.g., herpes simplex), inverted follicular keratosis (IFK), pemphigus, and Darier’s disease.

Bulla I. A bulla is a fluid-filled space in the epidermis or beneath it (see Fig. 6.5). 163

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TABLE 6.1  Conditions That Present With Eyelid Swelling Disease

Pathophysiology

Signs and Symptoms

Superficial Skin Processes Atopic dermatitis Basal cell carcinoma Capillary hemangioma

Skin manifestation of systemic allergic sensitivity Neoplastic changes Localized growth of capillaries

Contact dermatitis Herpes zoster ophthalmicus

Local reaction to irritative agent Varicella zoster virus infection

Periorbital ecchymosis (“black eye”)

Blunt trauma to orbit resulting in disruption of blood vessels Neoplastic changes

Raised, dry plaque Raised, umbilicated lesion with overlying telangiectasia Flat or raised well-circumscribed erythema; increases in size with crying Irritation, erythema, and edema Vesicles with surrounding erythema, possible bacterial superinfection; distributed unilaterally on forehead and upper eyelid in a dermatome Ecchymosis increasing in size over 48 hours, then slowly improving Painless erythematous flaky plaques, nodules, or ulcers

Squamous cell carcinoma Inflammatory Eyelid Processes Blepharitis

Dacryoadenitis

Inflammation of the base of the eyelashes and/or distal aspects of the eyelids; inflammation of the lacrimal gland Noninfectious obstruction of meibomian tear gland Inflammation of the lacrimal gland

Dacryocystitis

Inflammation of the lacrimal sac and duct

Hordeolum or stye

Hordeolum: infection of the meibomian (sebaceous) glands Stye: infection of the sweat gland (gland of Zeis) of the eyelid

Chalazion

Local Infections Orbital cellulitis

Preseptal cellulitis Mass Effect From the Orbit Autoimmune orbital mass effect Cavernous sinus thrombosis Endophthalmitis Orbital neoplasm

Irritated lid edges or eyelash

Discrete mass within the lid present for two or more weeks Circumscribed tender mass in upper outer lid; if advanced, may appear as the diffuse inflammation of preseptal cellulitis Tender mass at the medial aspect of the lower eyelid; if advanced, may appear as the diffuse inflammation of preseptal cellulitis Papule or furuncle at distal lid margin

Infection of the soft tissues within the orbit, posterior to the orbital septum, often due to spread from local sinus disease Infection of lid tissues around the orbit, often with local skin defect

Red, swollen, tender eyelid; extraocular movements limited because of pain or muscle edema; vision changes, diplopia; in children, fever and ill appearance Red, swollen, tender eyelid; full extraocular movements; no vision changes

Edema and inflammation of ocular muscles

Subacute onset bilateral proptosis, possible limited extraocular movements Headache, vomiting, vision changes, stupor

Thrombosed superior ophthalmic vein and cerebral veins Inflammation of the globe, often caused by penetrating trauma Tumor effect causing proptosis and affecting ocular muscle function and nerve function

Vision loss Subacute onset, unilateral, painless proptosis

(From Carlisle & Digiovanni: Differential diagnosis of the swollen red eyelid. Am Fam Physician 92(2):106–112, 2015. Table 1. American Academy of Family Physicians.)

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.

Terminology

Stratum corneum (keratin or horny layer) Epidermis

Stratum granulosum (granular layer) Stratum spinosum (squamous or prickle layer) Rete peg

Dermis (corium)

Stratum germinativum (basal layer) Sebaceous gland Hair shaft Apocrine sweat gland

Subcutaneous tissue

Adnexal epithelium Eccrine sweat gland Fig. 6.1  Normal layers of skin.

g p

m e

A

B

Fig. 6.2  Normal anatomy. A, Cross-section of the eyelid shows the inner white tarsal plate, the middle layers of muscle fibers, and the surface epithelium. Note the cilia coming out of the lid margin inferiorly. B, Histologic section shows the inner tarsal plate (p) containing the meibomian glands, the middle muscular bundles (m), and the surface epithelium (e). The cilia exit from the middle portion of the lid margin inferiorly. Apocrine sweat glands, eccrine sweat glands, sebaceous glands of Zeis, and hair follicles of the surface lanugo hairs are also seen in the lids (see also Figs. 1.27C and 7.1) (g, accessory lacrimal glands). (A, Courtesy of Dr. RC Eagle, Jr.)

A

B Fig. 6.3  Orthokeratosis, parakeratosis, and acanthosis. A, In this actinic keratosis, orthokeratosis (hyperkeratosis) is present (right half of picture) where the granular cell layer is prominent. Parakeratosis is present (left half of picture) where nuclei are retained in cells of keratin layer; granular cell layer is not prominent. B, In this squamous papilloma, acanthosis is present, especially on right side, evidenced by thickening of prickle-cell (squamous) layer. The granular cell layer is also thickened, and orthokeratosis is present.

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A

B Fig. 6.4  Dyskeratosis and atypical cells. A, In this case of hereditary benign intraepithelial dyskeratosis, keratinization of individual cells is present in the stratum spinosum (squamous or prickle-cell layer)—see also Fig. 7.19B. B, In this sebaceous gland carcinoma, many atypical cells are seen, including a tripolar mitotic figure.

Epithelium

Subepithelial tissue Subcorneal (under stratum corneum)

Primary cell damage

Acantholysis

Junctional

Fig. 6.5  Varieties of bullae encountered in skin.

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.

Leukoplakia I. Leukoplakia (white plaque) is a clinical term (not a histopathologic term) that is usually applied to mucous membrane lesions. The clinical appearance is caused by the orthokeratosis (hyperkeratosis). II. Clinically, any mucous membrane (conjunctival) lesion that contains orthokeratosis appears as a white plaque (leukoplakia; e.g., orthokeratosis induced by an underlying pinguecula, pterygium, papilloma, or carcinoma in situ).

Polarity I. Tissue polarity refers to the arrangement of epithelial cells in the epithelium (i.e., in normal polarity an orderly transition exists from basal cells to prickle [acanthocytes], to squamous cells, and so forth).

Congenital Abnormalities

II. Complete loss of polarity (see Fig. 7.24) has occurred when the cells at the surface are indistinguishable from the cells at the base (e.g., in squamous cell carcinoma). A. Spatial relationships between cells are also disturbed. B. Disorganized epithelial architecture is often a better means of diagnosing epithelial malignancy than is individual cell morphology.



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A. Positive staining for vimentin, S-100 protein, and antibodies against α and β crystalline lens proteins strongly support the lenticular anlage origin. It also may stain focally positively with glial fibrillary acidic protein (GFAP) and AE1/AE3. B. There may be psammoma body formation. C. Orbital phakomatous choristoma presenting as an eyelid mass with nasolacrimal duct obstruction has been reported.



CONGENITAL ABNORMALITIES Dermoid and Epidermoid Cysts

A phakomatous choristoma within the corneal stroma also has been reported.

See Chapter 14.

Phakomatous Choristoma I. Phakomatous choristoma (Zimmerman’s tumor) (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.

III. Electron microscopy reveals a thick homogeneous basement membrane, parallel intercellular border with interdigitations, cytoplasm with a paucity of organelles but the presence of microfilaments, and prominent basal lamina resembling lens capsule. IV. MRI demonstrates an inhomogeneously isointense appearance on T2-weighted sequences with fat suppression. There is a homogeneously low signal on T1-weighted sequences. Contrast-enhanced, fat-suppressed T1-weighted sequences

A

B

C

D Fig. 6.6  Phakomatous choristoma. A, Mass, present since birth, seen in lower lid of 10-week-old infant. B, Nests of benign cells resembling lens epithelial cells present in abnormal (choristomatous) location in dermis of lower lid. Periodic acid–Schiff-positive membrane mimics lens capsule. Anti-α lens protein (C) and anti-β crystallin (D) immunohistochemical stains are both positive. (Case presented by Dr. RC Eagle, Jr. to the meeting of the Verhoeff Society in 1992 and reported in Ellis FJ, Eagle RC, Shields JA et al.: Phakomatous choristoma (Zimmerman’s tumor). Ophthalmology 100:955, 1993.)

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show an inhomogeneous lesion with a clearly defined thick rim of contrast enhancement.

Miscellaneous Choristomas and Hamartomas I. Nevus lipomatosus (pedunculated nevus) is a gradually enlarging congenital eyelid papule. Histologically, the lesion is polypoid in shape and consisted 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 sebaceus syndrome. A. Encephalocraniocutaneous lipomatosis (Fishman syndrome or Haberland syndrome) is rare and characterized by involvement with congenital cutaneous, ocular, and neurologic abnormalities, particularly involving the head and neck. 1. This triad of organ system and regional involvement most frequently manifests itself as unilateral eye lesions in the form of choristomas, and skin lesions like lipomas, connective tissue nevi and alopecia, and ipsilateral cerebral involvement, such as porencephalic cysts, seizures, and mental retardation. 2. Eye lesions mainly include epibulbar or limbal dermoids; however, colobomas, corneal clouding, anterior chamber anomalies and globe calcification have been reported. 3. Visceral lipomas, nevus sebaceus and other organoid nevi also may occur. 4. Intracranial calcification has been reported. 5. The characteristic dermatologic finding is a hairless fatty tissue nevus of the scalp called nevus psiloliparus. 6. It is believed to be due to dysgenesis of the anterior neural tube and cephalic neural crest. B. Congenital lipoblastoma of the scalp and eyelid is very rare. Histopathologic examination shows lobular adipose tissue separated by fibrous septa. IV. Fibrous hamartoma of infancy is a rare, benign fibroproliferative lesion that develops during the first 2 years of life and up to 25% are congenital. A. Histopathologic findings are characterized by the presence of mature fibroblastic tissue, immature mesenchymal tissue, and mature adipose tissue. V. Nevus comedonicus A. Epidermal hamartoma characterized by groups of dilated follicular orifices resembling comedones that are filled with hyperkeratotic plugs. B. The lesion usually is unilateral; and seldom involves the eyelid.



C. May be activated during adolescence and can be complicated by bacterial superinfection. D. It may be associated with abnormalities of the central nervous system, eye (ipsilateral cataract and corneal changes), or skeletal system, and adnexal tumors. If accompanied by such changes it is known as NC syndrome. E. Histopathology demonstrates closely arranged, dilated follicular openings containing lamellar keratin and cystic formations. VI. 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. VII. Basaloid follicular hamartoma A. Rare benign hair follicle-derived neoplasm located in the superficial dermis. B. May be generalized or localized, familial or sporadic. C. May be associated with myasthenia gravis, systemic lupus erythematosus, and alopecia. D. The five clinical subtypes are: (1) solitary or multiple papules, (2) a localized plaque with alopecia, (3) a localized linear or unilateral papule or plaque, (4) a generalized dominantly inherited familial type without associated disorders, and (5) generalized papules associated with alopecia and myasthenia gravis. E. Thought to be an abnormal formation of vellus hair follicles and is limited to locations with preexisting hair follicles. F. Histopathology characterized by branching cords and anastomosing strands of basaloid cells in a loose, fibrous stroma. 1. Clefting between the tumor and adjacent stroma is minimal. 2. Horn cysts and pigment frequently are present. G. It can be confused with infundibulocystic basal cell carcinoma. H. Thought to be secondary to a less severe mutation in the patched (PTCH) gene on chromosome 9q23 than that attributed to basal cell carcinoma syndrome.

Cryptophthalmos (Ablepharon) I. Cryptophthalmos is a rare condition in which the embryonic lid folds fail to develop. II. Conjunctiva, cornea, and lid folds are replaced by skin that passes smoothly over the orbital margins. Palpebral structures and eyebrows cannot be identified. III. Because the cornea is not formed or is rudimentary, an incision through the skin covering the anterior orbit may enter directly into the inside of the eye.

Congenital Abnormalities

IV. Fraser syndrome (cryptophthalmos–syndactyly syndrome, Meyer–Schwickerath syndrome, Frasier–François syndrome, or Ullrich–Feichtiger syndrome) is characterized by cryptophthalmos, syndactyly, malformations of the eye, ear, larynx and genitourinary tract, umbilical hernia, renal agenesis, craniofacial dysmorphism, mental retardation, and musculoskeletal anomalies. A. Rare autosomal recessive disorder. B. A population-based study based on data from the European Surveillance of Congenital Anomalies (EUROCAT) birth defect registries identified 26 cases over an 18-year period. 1. The most common anomalies involved the eyes (83%), syndactyly (58%), and laryngeal anomalies (21%). Additionally, ambiguous genitalia were present in 13%. 2. Bilateral renal agenesis was found in 50% and unilateral in 17%. 3. Anorectal anomalies were present in 42%. 4. Eye anomalies were present in 83% of eyes and included: cryptophthalmos (75%); microphthalmos/ anophthalmos (33%); congenital cataract (8%); coloboma of iris (4%); coloboma of eyelid (4%); malformation of eyelids (8%); and retinal dysplasia (8%). C. Associated with the FRAS1 gene on the long arm of chromosome 4 (4q21), with FREM2 gene on chromosome 13, and with GRIp1 mutations of chromosome 12. D. Prenatal ultrasound can demonstrate characteristic features such as polyhydramnios or oligohydramnios, echogenic lungs, renal abnormalities or agenesis, and cryptophthalmos that can prove diagnostic for the disorder. Isolated bilateral complete cryptophthalmos has been reported.

V. Ablepharon macrostomia syndrome A. Overlaps clinically with Fraser syndrome, but is genetically distinct. Also phenotypically overlaps focal facial dermal dysplasias and Barber–Say syndrome. The latter is associated with a TWIST2 gene mutation and is characterized by hypertrichosis, redundant skin, and facial dysmorphism. 1. Proposed to be a separate entity within the group of FRAS–FREM complex disorders. 2. It has been suggested that ablepharon macrostomia and Barber–Say syndromes, however, could represent one syndrome. B. Characterized by severely shortened or absent eyelids (ablepharon), large mouth (macrostomia), abnormal external ears, hearing loss, absent zygomatic arches, umbilical abnormalities, growth retardation, hypertelorism, camptodactyly, syndactyly, foot abnormalities, redundant and dry skin, and genital malformations. C. It may have an autosomal dominant inheritance.

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Microblepharon I. Microblepharon is a rare condition in which the lids are usually normally formed but shortened; the shortening results in incomplete lid closure. II. When severe, it can be associated with significant ectropion and lagophthalmos, and can result in corneal exposure to infectious keratitis. III. Milder forms may be associated with absence of the lacrimal puncta and tetrastichiasis. IV. It can be seen in association with trisomy 12p.

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.

III. Colobomas of the upper and lower eyelids, upper eyelid and nasopalpebral lipomas, telecanthus, and maxillary hypoplasia are found in the nasopalpebral lipoma–coloboma syndrome.

Epicanthus I. Epicanthus consists of a rounded, downward-directed fold of skin covering the caruncular area of the eye. It is usually bilateral and is often inherited as an autosomal-dominant trait. A. It may be found in Ehlers–Danlos syndrome. B. Ptosis may be associated with epicanthus. II. Epicanthus inversus is an upward-directed, rounded fold of skin. A. It is seen as part of the blepharophimosis–ptosis–epicanthus syndrome (BPES). Telecanthus also is part of this syndrome. 1. Inherited as autosomal dominant and involves mutations in the forkhead box L2 (FOXL2) gene that result in two types of the disorder. a. Type 1 has the presence of premature ovarian failure and type 2 has the absence of such failure. Patients with both types have been identified in the same family. 2. 110 mutations involving 210 families worldwide have been identified for this disorder.

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3. Other ocular anomalies that may be associated with it are euryblepharon, amblyopia, microphthalmos, lacrimal drainage abnormality, extraocular muscle abnormalities, microcornea, trabecular dysgenesis, optic nerve hypoplasia, and colobomas of the optic disc. 4. Axenfeld–Rieger syndrome also has occurred with BPES. 5. A KAT6B mutation has been reported in BPES. B. BPES plus developmental anomalies of the ocular anterior segment, cleft lip and palate, and skeletal abnormalities are features of Michels syndrome. 1. Autosomal recessive inheritance. A de novo 3q22.3q24 microdeletion has resulted in features of blepharophimosis–ptosis–epicanthus inversus syndrome, Dandy–Walker malformation, and Wisconsin syndrome.

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

Lid Margin Anomalies I. Congenital entropion—this anomaly may result from an absence of the tarsal plate, or from hypertrophy of the tarsal plate or the marginal (ciliary) portion of the orbicularis muscle. II. Primary congenital ectropion (rare). A. Most cases are secondary to conditions such as microphthalmos, buphthalmos, or an orbitopalpebral cyst. B. Congenital entropion and atrichosis of the lower eyelids may be associated with tarsal hypoplasia. It may be an isolated occurrence or inherited as an autosomaldominant trait. C. Kabuki (make-up) syndrome includes characteristic facies with long palpebral fissures, everted lower lateral eyelids, and arched eyebrows. Systemic findings include mild to moderate mental retardation, fetal pads, and cleft palate. 1. Additionally, postnatal growth retardation, skeletal and visceral anomalies are present in a large percentage of patients. 2. It may be caused by mutations in one of two histone methyltransferase genes: KMT2D and KDM6A. 3. Production of the ocular phenotype may involve extensive interaction between KMT2D, WAR complex proteins, and PAXIP1. D. Oculoauriculofrontonasal syndrome can have features of oculoauriculovertebral spectrum and frontonasal dysplasia sequence. Findings have included preauricular skin tag, hypoplastic pinna lacking an ear canal, everted and hypoplastic eyelid, cleft lip and palate, bifid nasal tip, ocular hypertelorism, micrognathia, hypoplastic mandible, extra cervical rib, hemivertebrae, agenesis of the posterior corpus callosum with midline lipoma, and an extrarenal pelvis.

III. Ankyloblepharon—this defect consists of partial fusion of the lid margins, most commonly the temporal aspects.

Eyelash Anomalies I. Hypotrichosis (madarosis) A. Primary hypotrichosis (underdevelopment of the lashes) is rare. 1. Schopf–Schulz–Passarge syndrome (SSPS) is a rare ectodermal dysplasia characterized by hypodontia, hypotrichosis, nail dystrophy, palmoplantar keratoderma, and periocular and eyelid margin hidrocystomas. a. The hidrocystomas, in particular, are considered useful clues to diagnosing this disorder. b. Multiple palmoplantar eccrine syringofibroadenomas have also been associated with the syndrome. c. Autosomal recessive inheritance caused by mutations in the WNT10A gene. 1) SSPS and odonto-onycho-dermal dysplasia are considered variable expressions of the spectrum of WNT10A mutations. 2. GAPO syndrome is characterized by growth retardation (G), alopecia (A), pseudoanodontia (P) (failure of tooth eruption), and optic atrophy (O). a. Nonocular facial features include alopecia, frontal bossing, high forehead, midfacial hypoplasia, and thickened eyelids and lips. Specific ocular findings are hypertelorism, thickened and prominent upper eyelids, ptosis, white eyelashes (poliosis), strabismus, nystagmus, megalocornea, keratoconus, band keratopathy, interstitial keratitis, progressive optic atrophy, glaucoma, papilledema, and abnormal pattern visual evoked response. b. Mutations in ANTXR1 are causative for GAPO. B. Most cases are secondary to chronic blepharitis or any condition that causes lid margin scarring or lid neoplasms, e.g., sebaceous gland carcinoma. 1. 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 greater than 12 mm. 1. Congenital conditions associated with eyelash trichomegaly are Aghaei–Dastgheib syndrome, cone-rod dystrophy, congenital heart disease including tetralogy of Fallot, Cornelia de Lange syndrome, familial trichomegaly, Goldstein–Hutt syndrome, Hermansky– Pudlak syndrome, Oliver–McFarlane syndrome, and phylloid hypomelanosis. a. It is a characteristic finding in Oliver–McFarlane syndrome that also includes congenital hypopituitarism, and retinal degeneration with choroidal atrophy. b. It also may be associated with pigmentary retinopathy, dwarfism and mental retardation. Laurence– Moon syndrome is similar, but has progressive

Congenital Abnormalities

spinocerebellar ataxia and spastic paraplegia without trichomegaly. 2. Acquired eyelash trichomegaly has been associated with alopecia areata, atopic dermatitis/allergic disease, cancer (particularly metastatic renal adenocarcinoma), dermatomyositis, ectodermal dysplasia, anorexia nervosa, hypothyroidism, pregnancy, HIV, uveitis, and vernal keratoconjunctivitis. 3. Drugs associated with eyelash trichomegaly are cyclosporine, epidermal growth factor inhibitors including monoclonal antibodies and tyrosine kinase inhibitors, interferon alpha, topical prostaglandin analogs, tacrolimus, topiramate, and zidovudine. 4. It has followed recovery from diffuse hair loss secondary to transient malnutrition. 5. It may be a rare presenting sign of systemic lupus erythematosus. 6. Eyelash trichomegaly also may occur without other associated conditions. 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. 1. Afatinib has induced hypertrichosis of the eyelashes and eyebrows. 2. The autosomal-dominant disorder, stiff skin syndrome, is characterized by stone-hard indurations of the skin, mild hypertrichosis, and limitations of joint mobility with flexion contractures. a. Caused by mutations in the Arg-Gly-Asp (RGD) sequence encoding domain of fibrillin 1 (FBN1) gene that mediates integrin binding. 3. 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 sporadic or hereditary. a. Lymphedema distichiasis syndrome is a rare variably penetrant autosomal dominant genetic disorder characterized by pubertal onset lower limb lymphedema and distichiasis. It must be distinguished from the congenital lymphedema found in Milroy disease. 1) Distichiasis is present in 90%–95% of patients. There is associated chronic keratitis, conjunctivitis and photophobia in 75% of cases. 2) Other associated findings may be varicose veins, cleft palate, congenital heart disease defects, ptosis, and renal anomalies. 3) FOXC2 mutations can result in this syndrome. It has been postulated that either a complete loss or a significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation leading to lymphedema. b. Familial distichiasis without lymphedema and caused by FOXC2 gene mutations has been reported. Conversely, hereditary lymphedema

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caused by FOXC2 mutation and unaccompanied by distichiasis also occurs. c. Late-onset hereditary lymphedema (see section on Congenital Conjunctival Lymphedema in Chapter 7) has been reported. It has been questioned if the eyelash findings in that report really represent distichiasis, and it has been suggested that it was not distichiasis lymphedema syndrome. d. The 22q11.2 deletion syndrome is the most common microdeletion syndrome. 1) It is associated with facial and ocular anomalies including eyelid abnormalities (distichiasis, hooding, narrow palpebral fissure, telecanthus, blepharitis, hypertelorism, and thin eyebrows and eyelashes and ocular abnormalities such as posterior embryotoxon, tortuous retinal vessels, refractive errors, iris remnants, and strabismus. 2) Findings present in 50% or more patients include tortuous retinal vessels, eyelid hooding, narrow palpebral fissure, and posterior embryotoxon. 3) Multiple systemic anomalies also can be found. e. Blepharo-cheilo-dontic syndrome is characterized by distichiasis, lagophthalmos, euryblepharon (excess horizontal eyelid length and decreased vertical eyelid skin), ectropion of the lower eyelids, bilateral cleft lip and palate, and oligodontia (congenital absence of 6 or more teeth). f. Histopathologic examination of congenital distichiasis has found the lashes to emerge from the ducts of the tarsal meibomian glands. 1) Multiple hair shafts may emerge from a single duct lumen. 2) Changes of extensive fibrosis, and inflammation may be secondary if previous epilation has occurred. 3) It has been postulated that the histopathologic findings represent a failure of the primary epithelial cells to differentiate selectively into a sebaceous gland only resulting in complete pilosebaceous units. 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. Ectopic cilia represents a rare condition. C. Most commonly appears as an abnormal growth of eyelashes on the external, lateral quadrant of the upper eyelid, or the internal, conjunctival surface of the eyelid. D. The lesion has presented in association with an orbital dermoid cyst. E. It has been postulated that these lesions arise in the eyelid skin and not with metaplastic meibomian glands. F. A case of complex eyelid choristoma containing ectopic cilia and a functioning lacrimal gland has been reported.

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Ptosis

1. Nonsyndromic ichthyosis a. Common ichthyoses. Among the nonsyndromic ichthyoses, ichthyosis vulgaris (IV) and X-linked recessive ichthyosis (XLRI) were designated as “common ichthyoses.” 1) IV has an incidence of 1 in 250 births and usually is a milder form of the disorder. It is caused by autosomal dominant mutations in the filaggrin gene (FLG), which is involved in epidermal differentiation and formation of the skin barrier. 2) XLRI is the second most common form of inherited ichthyosis and occurs in 1 : 2000 to 1 : 6000 males. Clinically, it resembles IV. It is caused by mutations in the STS gene on the X chromosome, which encodes steroid sulfatase. b. Autosomal recessive congenital ichthyosis (ARCI). 1) Has been described as a genetically and phenotypically heterogeneous group of disorders that include harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE).



I. Ptosis is a condition in which lid elevation is partially or completely impaired. II. It may be congenital, associated with other anomalies, or caused by trauma, third cranial nerve damage, or many other causes. III. Histologically, the levator muscle may show atrophy or may appear normal.

Ichthyosis Congenita I. Ichthyosis (Fig. 6.7) A. In 2009, the First Ichthyosis Consensus Conference in Sorèze standardized the classification and nomenclature for ichthyosis. The classification is comprehensive and a bit intimidating for the nonspecialist in that area. The reader is referred to the article by Marukian and Choate in the bibliography for this chapter for an excellent summary upon which much of the present section has been derived. The Consensus Conference divided the disorder into two main groups: nonsyndromic and syndromic types.



A

B

C

D Fig. 6.7  Ichthyosis congenita. A, Child has severe ichthyosis congenita. B and C, Right and left eyes show thickened, scaly skin and keratinization (white-gray plaques) of palpebral conjunctiva. D, Thickened epidermis and very prominent granular cell and keratin layers are seen (conjunctiva also showed papillary reaction with keratinization). (D, Modified from Katowitz JA, Yolles EA, Yanoff M: Ichthyosis congenita. Arch Ophthalmol 91:208, with permission. © American Medical Association 1974. All rights reserved.)

Congenital Abnormalities

2) The incidence of ARCI is 1 : 200,000 births. 3) HI is caused by loss-of-function mutations in ABCA12, which encodes an ATP-binding cassette (ABC) transporter. 4) LI and CIE are said to represent a spectrum of disorders most caused by mutations in one of the following genes: TGM1, NIPAL4/ ICHTHYIN, ALOX12B, ALOXE3, CYP4F22, ABCA12, PNPLA1, CERS3, and LIPN. The most common mutations involve TGM1. c. Keratinopathic ichthyosis is a group of entities caused by mutations in the keratin family of genes and includes epidermolytic ichthyosis (EI), which is caused by autosomal dominant mutations in the keratin 1 (KRT1) and (KRT10) genes, that are important for maintaining structural integrity in suprabasal keratinocytes. Minor variants include superficial EI, annular EI, and ichthyosis Curth–Macklin. d. Autosomal recessive congenital ichthyosis is caused by mutations in the PNPLA1 gene. e. Erythrokeratodermia variabilis is caused by mutations in the GJA1 gene. f. Pityriasis rubra pilaris is due to mutations in the CARD14 gene. g. The most common gene involved in bathing-suit ichthyosis is the transglutaminase-1 gene (TGM1). 2. Syndromic ichthyosis includes CHILD syndrome (NSDHL mutations), Conradi–Hunermann–Happle syndrome and CHILD syndrome (EBP mutations), and Sjögren-Larson syndrome (ALDH3A2 mutations). a. These entities involve one or more organ systems in addition to their skin manifestations. b. Other syndromic ichthyoses are erythrokeratodermia–cardiomyopathy syndrome caused by mutations in DSP, which encodes desmoplakin, a primary component of desmosomes, and the syndrome of ichthyosis, intellectual disability, and spastic quadriplegia that is caused by mutations in the ELOVL4 gene. 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. 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 syndrome), keratosis palmaris et plantaris, keratosis follicularis spinulosa decalvans (Siemens’ disease), epidermolysis bullosa, and the syndrome of

173

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.

Xeroderma Pigmentosum I. Xeroderma pigmentosum (XP) is one of the inherited DNA repair disorders, which also include Cockayne syndrome, trichothiodystrophy, Bloom syndrome, Rothmund–Thomson syndrome, and Werner syndrome. A. They can be differentiated by DNA analysis. XP is inherited as an autosomal-recessive disorder, is characterized by a hypersensitivity of the skin to ultraviolet radiation, a deficiency in the repair of damaged DNA, and a resultant high incidence of skin cancers. B. Associated with 7 genes (XPA–XPG) having a defect in nucleotide excision repair (NER) or an eighth gene, XPV, that has a defect in polymerase η. Squamous and basal cell carcinomas, fibrosarcoma, and malignant melanoma may all develop on areas of skin exposed to sun.



C. Patients with XP have a 1000-fold increase in skin cancers caused by UV-irradiation. The lesions may arise in the early first decade of life. II. Skin lesions show three stages: mild, diffuse erythema associated with scaling and tiny, hyperpigmented macules; atrophy of the skin, mottled pigmentation, and telangiectasis—the picture resembles radiation dermatitis; and development of skin malignancies. III. In addition to the eyelid skin, there may be corneal and conjunctival involvement; however, intraocular structures usually are not affected. Patients may have photophobia and tearing accompanied by blurred vision, corneal clouding and corneal injection, and pterygium formation. IV. CNS manifestations involve 30% of patients. The defective NER pathway is associated with neurodegenerative disorders possibly related to oxidative stress. V. The disease ultimately is fatal; however, survival can be prolonged by careful follow-up and simple preventive measures to prevent sun exposure.

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VI. Histology A. Early, the epidermis shows orthokeratotic and atrophic foci associated with epidermal cells and macrophages showing pigment phagocytosis. Subepidermal perivascular infiltrates of lymphocytes and plasma cells are found. B. Later, the orthokeratosis and pigment deposition become more marked. An associated acanthosis of the epidermis and basophilic degeneration of the collagen are found in the corium. C. The histopathologic appearance of the malignancies is identical to that in patients who do not have xeroderma pigmentosum.

AGING Atrophy See subsection Atrophy, earlier, under Terminology. I. Skin aging can be divided into intrinsic aging due to normal maturation and extrinsic aging due to factors such as sun exposure, smoking, and environmental pollutants. A. These extrinsic factors are significant, and are reflected in such histopathologic changes as solar elastosis that, in turn, contribute to the overall clinical appearance of aging skin (see section on Dermatochalasis in this chapter). B. Moreover, they can be important risk factors for the development of pathologic conditions, such as skin tumors, that also will be discussed later in this chapter. II. “Aging” skin appears dry, rough, wrinkled, lax, and unevenly pigmented. III. Because the collagen of the corium is altered, it stains basophilic instead of eosinophilic with hematoxylin and eosin. The collagen stains positively for elastin; the positivity is not changed if the tissue is pretreated with elastase. It is the altered staining characteristic of the corium that has led to the use of terms such as basophilic degeneration, actinic changes, and senile elastosis.

A

IV. The elastic tissue is also altered and increased. It, along with the changed collagen, helps to explain the characteristic wrinkling of senile skin. V. Overall, the periorbital skin aging process is marked by decreased skin resilience, secondary to loss of skin surface texture, loss of epidermal–dermal connections and dermal compactness, all of which lead to the multilayered structure of the skin becoming separated.

Senile Ectropion and Entropion I. An accentuation of the aging changes may result in an ectropion (turning-out) or an entropion (turning-in) of the lower lid. A. Reduction in collagen and elastic fibers may contribute to horizontal eyelid laxity in involutional eyelid entropion and ectropion. B. Upregulation of elastolytic enzymes may contribute to elastic fiber degeneration in patients with involutional ectropion and entropion. II. Histologically, both ectropion and entropion show chronic nongranulomatous inflammation and cicatrization of the skin and conjunctiva. A. Ectropion exhibits increased orbicularis and Riolan’s muscle ischemia, fragmentation of elastic and collagenous tissues in the orbital septum and tarsus, and hypertrophy of the tarsus. Actinic damage of the anterior eyelid lamella of the lower eyelid has been cited as a contributing factor in patients with involutional eyelid changes, and is most marked in those with ectropion. B. Entropion shows increased atrophy of the orbital septum and tarsus.

Dermatochalasis and Blepharochalasis 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. A. Risk factors include age, male sex, lighter skin color, and higher body mass index.

B Fig. 6.8  Dermatochalasis. A, Lax, redundant lid skin is hanging in folds and partially occludes pupils. A blepharoplasty was performed. B, Histologic section shows an atrophic, thin, smooth epidermis with a decrease in the number and size of the rete pegs. The corium shows some loss of elastic and collagen tissue, as well as basophilic degeneration of the collagen, along with an increase in capillary vascularity and a mild lymphocytic inflammatory reaction.

Aging



B. Severe dermatochalasis can alter the biomechanical properties of the cornea such that there is a positive Corneal Resistance Factor in patients with the disorder, but negative in normal individuals and those with mildto-moderate dermatochalasis. C. 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, and basophilic degeneration of the collagen (actinic elastosis), and a mild lymphocytic inflammatory reaction. Moreover, there is an increase in the number of lymphatic vessels, disarrangement of collagen fibers, stromal edema, and increased number of macrophages. II. Blepharochalasis A. 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. B. Three stages have been identified: (1) primary edema with painless and transient swelling of the eyelids accompanied by mild redness of the skin resembling angioedema, (2) the atonic ptosis stage is characterized by skin changes of reddish brown discoloration, venular prominence, lax skin that may override the eyelashes, and (3) relaxation of the orbital septum resulting in prolapse of orbital fat and lacrimal glands with secondary drooping of the affected eyelid. C. Others have used a two-stage categorization: (1) early stage with nonpitting eyelid edema, and (2) late stage with either constant swelling accompanied by lid skin laxity and loose folds or by discoloration, thinning, and atrophy of lid tissue that can result in a characteristic tissue paper appearance to the skin and ptosis. The skin can have tortuous vessels. D. 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. E. It may be accompanied by ptosis, acquired blepharophimosis secondary to changes in the canthal tendons, herniation of orbital fat, or lacrimal gland prolapse. F. Some have considered it to be a variant of cutis laxa (see below). G. Histopathologic examination of a specimen from a 23-year-old black female disclosed complete absence of elastic fibers. There also was mild inflammatory infiltrate of lymphocytes and multinucleated histiocytes, dermal edema, and rare dilated vessels suggesting lymphedema. A neutrophil infiltrate also has been reported. 1. Other specimens have demonstrated atrophy, fragmentation, and markedly decreased amounts of elastic fibers in the dermis.













175

2. Electron microscopy has confirmed lack of elastic fibers in the involved skin in a patient with bilateral blepharochalasis. 3. Chronic inflammation frequently is found. 4. Collagen is loose and appears atrophic. 5. Elastic fibers decrease in the tendons of external orbital muscles, which elongate. H. Immunofluorescence localization of IgA deposits in blepharochalasis suggests an immunologic basis for the disorder. 1. Matrix metalloproteinases, particularly MMP-3 and MMP-9 may play a part in the pathobiology of blepharochalasis. I. Ascher syndrome (Laffer–Ascher syndrome) is characterized by blepharochalasis, double lip and nontoxic goiter. Goiter is found in 10%–50% of cases. 1. Other findings may include iris coloboma, iris heterochromia, narrowed horizontal palpebral fissures, and decreased intercanthal distance. 2. There may be eyelid ectropion or entropion with trichiasis. 3. The double lip-appearance is secondary to an overgrowth of lip mucosa. a. Double lip also may be found as an isolated nonsyndromic isolated occurrence. It may be associated with bifid uvula or cleft palate. J. Melkersson–Rosenthal (MK) syndrome (triad of recurrent labial edema, relapsing facial paralysis, and fissured tongue) also can present with eyelid edema of “unknown cause.” 1. It has an incidence of 1 : 1250. 2. It may be isolated or seen in association with chronic diseases such as Down’s syndrome, sarcoidosis, multiple sclerosis, HIV, autoimmune thyroiditis, ocular palsies, and diabetes mellitus. 3. Non-necrotizing granulomatous inflammation is associated with this disorder. 4. It may be caused by mutations in the FATP1 gene. K. Blau syndrome has similarities to Melkersson–Rosenthal syndrome. Blau syndrome is autosomal dominant and includes granulomatous inflammation in the skin, granulomatous iridocyclitis, and granulomatous arthritis with camptodactyly. It is associated with mutations in the CARD15/NOD2 gene complex and may be linked to Crohn’s disease. L. Mounier–Kuhn also has similarities to MK syndrome and is associated with congenital tracheo-bronchomegaly.

Herniation of Orbital Fat I. Defects or dehiscences in the orbital septum produced by aging changes, often associated with dermatochalasis, may result in herniated orbital fat, simulating an orbital lipoma. II. Comprises 2% of orbital tumors. The lesion may be associated with ptosis, dermatochalasis, chemosis, proptosis and diplopia. III. Histologically, mature fat is found, which looks similar to that in a lipoma. Examination of 21 specimens, in one

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CHAPTER 6  Skin and Lacrimal Drainage System

study, demonstrated the presence of distinct lobules of fairly uniform-sized mature adipocytes, that are separated by delicate fibrovascular septae containing small normochromatic fibroblast cells with a background of collagen. A. Hyperchromatic stromal cells and “wirelike” collagen was absent. B. The adipocytes contained intranuclear vacuoles (Lochkern cells). C. There were no true lipoblasts. D. A characteristic feature was the presence of multinucleated giant cells containing a wreathlike arrangement of uniform, small, normochromatic nuclei (floretlike giant cells) located within and adjacent to the fibrous septae. E. Faint intranuclear vacuoles within the nuclei of the giant cells were said to give them a “bubbly” appearance. F. Chronic inflammation may be present. G. On immunohistochemical staining, the floretlike giant cells expressed CD34 and vimentin, but the Lochkern cells were positive for CD34, S100 protein, and vimentin. H. CD68 was positive in histiocytes and stromal cells were negative for MIB1. IV. Analysis of herniated orbital fat for chromosomal abnormalities was negative for copy number gains or losses suggesting that orbital fat herniation is a reactive process. The distinction between a primary orbital lipoma and herniated orbital fat often is made more readily clinically than histologically.

Floppy Eyelid Syndrome I. Floppy eyelid syndrome is characterized by loss of rigidity in the tarsal plate of the upper eyelid so that it can be everted easily and folded upon itself. It is one of the conditions recognized as a lax eyelid syndrome. II. Papillary conjunctivitis has been associated with the disorder from its initial description. A. Punctate epithelial keratopathy is seen in 45% of patients. B. Keratoconus is an associated finding in 10%. C. Similar findings have been reported by others. D. Numerous additional corneal complications have been associated with FES. III. FES most often is found in obese males. A. FES also has been associated with obstructive sleep apnea (OSA). B. Some have suggested a common pathogenic mechanism such as abnormal tissue elasticity. C. Others, however, contend that the association represents a mutual relationship to obesity, and reflects more the patient’s preference as to side of the body and secondary eyelid eversion rather than an underlying pathobiologic relationship. D. There also is an increased incidence of lid laxity and OSA in patients with keratoconus. E. OSA also is associated with reduced tear break-up time and lacrimal gland prolapse.



F. OSA does not necessarily correlate with other forms of ocular surface disease. IV. Globe luxation, either spontaneous or voluntary, may be seen in FES, and may be associated with secondary optic neuropathy. V. Eyelash ptosis and loss of eyelash parallelism affects 97% of patients with FES. VI. Plasma leptin levels are elevated in 64% of patients, and all these patients have a high Body Mass Index. VII. FES may be associated with glaucoma in patients with OSA. VIII. Corneal hysteresis is lower in patients with FES than in normal controls. IX. Histopathologic examination of the involved tarsal plate reveals a decreased number of mature elastic fibers and an increased abundance of oxytalan compared to upper eyelid control specimens. A. There is increased staining for collagens I and II. B. There is no difference in staining for CD3, CD20, or CD68 expressing cells in comparison to controls. X. Upregulation of elastolytic enzymes, probably related to repeated mechanical stress, has been postulated to participate in elastic fiber degradation and subsequent tarsal laxity with eyelash ptosis in floppy-eyelid syndrome.

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 (see above).



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

Inflammation





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.

177

A

B

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.

Fig. 6.9  Hordeolum. A, The patient complained of swelling, redness, and pain in the right lower lid over a few days. The inflammation is mainly located in the outer layers of the lid and is called an external hordeolum. Similar inflammation in the inner layers is called an internal hordeolum. B, Histologic section of another case shows a purulent exudate consisting of polymorphonuclear leukocytes and cellular debris.

A lipogranuloma is composed of an extracellular accumulation of fat, while a xanthoma 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).

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A

B

Fig. 6.10  Chalazion. A, The hard, painless lump was present in the left lower lid for at least a few weeks. B, Histologic section shows a clear circular area surrounded by epithelioid cells and multinucleated giant cells. In processing the tissue, fat is dissolved out, and the area where the fat had been appears clear. C, Fresh frozen tissue that has not been processed through solvents stains positively for fat in the circular areas. (C, Oil red-O stain.)

C

f pl e

c

p

A

B Fig. 6.11  Granuloma pyogenicum. A, The patient who had a hard, painless lump in the right lower lid for more than one month presented complaining of a red, fleshy area inside the lid. B, Histologic section shows a vascularized tissue (granulation tissue) that consists of inflammatory cells (plasma cells [p] and polymorphonuclear lymphocytes [pl]), fibroblasts (f), and the endothelial cells (e) of budding capillaries (c).

V. Acne rosacea A. Acne rosacea affects mainly the skin of the middle face, nose, cheeks, forehead, and chin, and 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). Other microbial agents, such as Staphylococcus epidermidis also may be involved.



B. Ocular involvement is commonly found and consists of blepharitis, chalazion, conjunctival and lid granulomas, episcleritis, hyperemic conjunctivitis, internal

Inflammation

hordeolum, keratitis, lid margin telangiectasis, meibomianitis, squamous metaplasia of the meibomian duct, and superficial punctate keratopathy. There is associated loss of meibomian gland tissue as reflected in reduced meibomian gland area and decreased meibomian gland density. 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 section in this chapter.

179

Viral Diseases I. Molluscum contagiosum (Fig. 6.12) A. Clinically, a dome-shaped, small (1 to 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

A

B

C

D Fig. 6.12  Molluscum contagiosum. A, Lesion of molluscum contagiosum on upper-lid margin had caused follicular conjunctival reaction in inferior bulbar conjunctiva. B, Increased magnification shows an umbilicated lesion that contains whitish packets of material. C, Typical molluscum bodies present in epithelium. D, Intracytoplasmic, small, eosinophilic molluscum bodies occur in the deep layers of epidermis. The bodies become enormous and basophilic near the surface. The bodies may be shed into the tear film, where they cause a secondary, irritative follicular conjunctivitis. (A and B, Courtesy of Dr. WC Frayer.)

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CHAPTER 6  Skin and Lacrimal Drainage System present initially with molluscum eyelid lesions. In addition, multiple epibulbar molluscum lesions have been reported in association with atopic dermatitis.









B. When the eyelids of HIV patients are infected with molluscum, the lesions can be disfiguring and may even obstruct vision. C. Desmoplastic trichilemmoma may resemble molluscum clinically. D. 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.

A



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 intraepidermal 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 with 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.

B

Fig. 6.13  Verruca vulgaris. A, Clinical appearance of a typical “warty” lesion near the lid margin. B, Histologic section demonstrates papillomatous lesion with marked orthokeratosis (hyperkeratosis) and elongated rete ridges characteristically bent inward (i.e., radiating toward central focus). C, High magnification shows acanthosis, orthokeratosis (hyperkeratosis), intracellular darkstaining keratohyaline granules, and occasional intranuclear eosinophilic inclusion bodies, which represent virus inclusions. Most vacuolated cells contain smaller eosinophilic particles, probably representing degenerative products.

C

Inflammation

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 steelgray 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).

Bacterial Diseases I. Impetigo A. Impetigo may be caused by staphylococci or streptococci (less common), both of which cause a bullous eruption. B. Histologically, a superficial bulla directly under the keratin layer is filled with polymorphonuclear leukocytes; cocci are found in neutrophils or free in the bulla. II. Staphylococcus—see under Impetigo (previous entry) and Blepharoconjunctivitis (see elsewhere in this chapter). III. Parinaud’s oculoglandular syndrome (see Chapter 7).

A

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. D. 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.

B

Fig. 6.14  Demodex folliculorum. Demodex seen in hair follicle (A) and in sebaceous gland of hair follicle (B). Tiny dots represent nuclei of mite. C, Photomicrograph of mite. (C, Courtesy of Dr. HJ Nevyas.)

C

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A

B Fig. 6.15  Phthirus pubis. A, One crab louse and many nits (ova) are present among the lashes toward the lid margin. B, Different view of the crab louse.

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 syndrome (EDS) consists of a rare, heterogeneous group of disorders characterized by loosejointedness, 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. II. A 2017 International Classification of the Ehlers–Danlos Syndromes has been published (Table 6.2). A. It divides EDS into 13 clinical subtypes. B. Additionally, it presents a regrouping according to the underlying genetic and pathogenic mechanisms. C. In this scheme, classical EDS is characterized by autosomal dominant inheritance involving primarily COL5A1 and type V collagen. D. Rarely, type I collagen also may be involved in classical EDS. E. Also of import from an ocular perspective is the subtype brittle cornea syndrome, which is autosomal recessive and involves the genes ZNF469 and PRDM5, and their associated proteins.



F. The skin in EDS is hyperextensible, but not lax. 1. When it is pulled, it stretches; when let go, it quickly springs to the original position. 2. The skin in cutis laxa (see subsection Cutis Laxa, later in this chapter), on the other hand, tends to return slowly after it is pulled. III. The most common ocular findings are deep-set eyes, infraorbital creases, blepharochalasis, palpebral ptosis, and epicanthal folds. Other changes may be 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.

Cutis Laxa I. Cutis laxa syndromes are multisystem disorders (Fig. 6.16) that share a common feature of extensible skin that hangs in loose folds over all parts of the body, especially in those areas where it is normally loose (e.g., around the eyes). A. The lungs may be involved, causing emphysema. B. Cor pulmonale may result in early death. C. Autosomal-dominant, recessive, and acquired forms have been reported. Rarely, it is found to involve only the face without a preceding inflammatory condition or systemic involvement.

II. The basic defect seems to be in the elastic fibers, which are reduced in number, shortened, and show granular degeneration. III. Ocular findings include hypertelorism, blepharochalasis, ectropion, and corneal opacities. IV. Histologically, the skin shows fragmentation and granular degeneration of the dermal elastic tissue, along with an increase in the amount of dermal ground substance. V. The underlying molecular defects in these disorders involve all steps in elastic fiber assembly.

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TABLE 6.2  Clinical Classification of the Ehlers–Danlos Syndromes, Inheritance Pattern, and

Genetic Basis

Clinical EDS Subtype

Abbreviation

IP

Genetic Basis

Protein

1

Classical EDS

cEDS

AD

Type V collagen Type I collagen

2 3

Classical-like EDS Cardiac-valvular

clEDS cvEDS

AR AR

4

Vascular EDS

vEDS

AD

5 6 7 8

Hypermobile EDS Arthrochalasia EDS Dermatosparaxis EDS Kyphoscoliotic EDS

hEDS aEDS dEDS kEDS

AD AD AR AR

9

Brittle Cornea syndrome

BCS

AR

10

Spondylodysplastic EDS

spEDS

AR

11

Musculocontractural EDS

mcEDS

AR

12 13

Myopathic EDS Periodontal EDS

mEDS pEDS

AD or AR AD

Major: COL5A1, COL5A1 Rare: COL1A1 c.934C>T, p.(Arg312Cys) TNXB COL1A2 (biallelic mutations that lead to COL1A2 NMD and absence of pro a2(I) collagen chains) Major: COL3A1 Rare: COL1A1 c.934C>T, p.(Arg312Cys) c.1720C>T, p.(Arg574Cys) c.3227C>T, p.(Arg1093Cys) Unknown COL1A1, COL1A2 ADAMTS2 PLOD1 FKBP14 ZNF469 PRDM5 β4GALT7 β3GALT6 SLC39A13 CHST14 DSE COL12A1 C1R C1S

Tenascin XB Type I collagen Type III collagen Type I collagen

Unknown Type I collagen ADAMTS-2 LH1 FKBP22 ZNF469 PRDM5 β4GalT7 β3GalT6 ZIP13 D4ST1 DSE Type XII collagen C1r C1s

AD, autosomal dominant; AR, autosomal recessive; IP, inheritance pattern; NMD, nonsense-mediated mRNA decay. (From Malfait et al.: The 2017 International Classification of the Ehlers–Danlos Syndromes. Am J Med Genet Part C (Seminars in Medical Genetics) 175C:8–26, 2017. Wiley.)

Pseudoxanthoma Elasticum I. Pseudoxanthoma elasticum (PXE) is inherited in an autosomal-recessive manner. A. The classic triad is involvement of the skin, the eyes, and the cardiovascular system. The gastrointestinal tract also may be involved. B. Linkage analysis and mutation detection techniques have shown mutations in the ATP-binding cassette (ABC) transporter gene ABCC6 on chromosome 16. 1. ABCC6 gene mutations account for 90%–95% of affected individuals. 2. A PXE-like disease has been identified that has coagulation factor deficiencies. a. It is caused by mutations in the gamma-glutamyl carboxylase (GGCX) gene. b. This mutation also points up the importance of vitamin-dependent inhibitors of mineralization, such as matrix Gla protein (MGP). 3. ABCC6 and GGCX genes may interact with GGCX acting as modifiers of ABCC6. 4. Mutations in the ENPP1 gene, which codes for the enzyme ectonucleotide pyrophosphatase phosphodiesterase 1, also may interact with ABCC6. ENPP1 mutations may cause a rare form of PXE.







5. There probably are other genetic or environmental modifiers to induce phenotypic variability in PXE. C. The prevalence is between 1 : 25,000 and 1 : 100,000. D. 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, yellowish (resembling chicken skin) papules. 1. The lateral side is affected first, often followed by the axillae. 2. The skin in the involved areas becomes lax, redundant, and relatively inelastic. 3. The skin changes may not be noted until the second decade of life or later. E. The ocular fundus shows angioid streaks (see Fig. 11.40), sometimes with subretinal neovascularization (see discussion in Chapter 11). 1. In one study, angioid streaks were found in 93.75% of patients. 2. Neovascularization occurred at a mean age of 44.28 years. It is frequent and is associated with poor vision. a. Examination of the fundus also may show a background pattern, called peau d’orange, in the

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A

B

C

D Fig. 6.16  Cutis laxa. A, Pulling easily extends loose skin of face. B, Corneal opacities occur in all layers of stroma. C, Skin appears relatively normal at low magnification. D, Verhoeff’s elastica stain shows fragmentation and granular degeneration of dermal elastic tissue. (A and B, Courtesy of Dr. JA Katowitz.)

posterior aspect of the eyes, caused by multiple breaks in Bruch’s membrane. b. The optic nerve may contain drusen, which were found in 16.9% of patients in one study. Drusen of the optic nerve occur 20 to 50 times more often in pseudoxanthoma elasticum than in the general, healthy population. F. There is increased risk of atherosclerosis. Cardiovascular system manifestations include increased risk of stroke, hypertension, weak or absent peripheral pulses, intermittent claudication, angina pectoris, and internal hemorrhages. II. There is progressive calcification of connective tissue rich in elastic fibers. The basic defect seems to be related to progressive calcification. III. Histologically, the amount of elastin is elevated. A. The skin shows elastin abnormalities only in the midepidermis, with elastin band swelling, granular degeneration, and fragmentation. B. The elastin fibers may become calcified. C. Normal elastin and collagen is present above and below the affected zone. D. Clumping and calcification of elastin are only present in homozygous individuals and only in clinically affected skin.

E. Angioid streaks consist of breaks in Bruch’s membrane. IV. Transmission electron microscopic (TEM) evaluation demonstrates aberrant elastic fibers with an irregular outline and heterogenic inner structures. A. Collagen fibers have normal structure with irregular distribution. B. Scanning electron microscopy shows disorganization of collagen fibers and small “stone-like” deposits that measure 5 µm associated with bigger structures ranging from 10–15 µm. C. The smaller structures have a polyhedral shape or are squared. D. These structures have been interpreted as representing altered elastic fibers seen on TEM.

Erythema Multiforme I. Erythema multiforme (EM), an acute, self-limited dermatosis, is a common-pathway, cutaneous reaction to drugs, viral or bacterial infections, or unknown causes. More than 90% of EM is caused by infections, especially herpesvirus infection; however, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are related to drugs in more than 95% of cases (see below). II. Erythema multiforme shows multiform lesions of macules, papules (most common lesion), vesicles, and bullae.

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185

TABLE 6.3  Differential Diagnosis of SJS/TEN Disease

Mucositis

Morphology

Onset

Drug-induced pemphigoid Staphylococcal scalded skin syndrome Drug-induced pemphigus Drug-triggered pemphigus Paraneoplastic pemphigus Acute graft versus host disease Acute generalized exanthematous pustulosis Drug-induced linear IgA bullous dermatosis

Rare Absent Usually absent Present Present (usually severe) Present Rare Rare

Tense bullae, sometimes hemorrhagic Erythema, skin tenderness, perioral crusting Erosions, crusts, patchy erythema Mucosal erosions, flaccid bullae Polymorphous skin lesions, flaccid bullae Morbilliform rash, bullae, and erosions Superficial pustules (resembles pustular psoriasis) Tense, subepidermal bullae (resembles pemphigoid)

Acute Acute Gradual Gradual Gradual Acute Acute Acute

(From Kohanim et al.: Stevens Johnson syndrome/toxic epidermal necrolysis-A comprehensive review and guide to therapy. I. Systemic Disease. The Ocular Surface 14(1):2–19, 2016. Table 3. Elsevier.)

Characteristic “target” lesions are noted as round to oval erythematous plaques that contain central darkening and marginal erythema.

III. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are often viewed as ends of a continuum and are discussed concurrently (Table 6.3). A. Mortality rates may be as high as 35%. B. They are characterized in the acute phase by a febrile cold-like illness followed by skin and mucous membrane necrosis and detachment. C. The associated keratinocyte death and epidermal necrosis result in splitting of the subepidermal layers with resulting loss at skin and mucosal surfaces. D. These changes are described as rapid and irreversible, and may lead to severe morbidity and even death. E. Classification 1. If less than 10% of the body surface area (BSA) is involved the disease is termed SJS. 2. If greater than 30% of the BSA is involved it is TEN. 3. Those patients with BSA involvement between 10% and 30% are categorized as having SJS-TEN overlap. F. The worldwide incidence of SJS and TEN is estimated to be 1.9 per million individuals. G. They are delayed hypersensitivity reactions. 1. There are genetic predispositions to these disorders, which commonly are precipitated by medications, particularly cold medications such as dipyrone, NSAIDs and cold medication ingredients such as acetaminophen. 2. Viral infections also may be involved, and have been postulated to predispose patients to medication reactions by altering the inflammatory and immunologic homeostasis. 3. The genetic risk factors are drug-specific, and vary among populations and/or ethnic groups. 4. Younger patient age, and patient exposure to NSAIDS or cold remedies may be predictive of acute ocular severity. 5. SJS/TEN also may be triggered by malignancies. H. The keratinocyte apoptosis seen in SJS/TEN is thought to occur through T-cell mediated Fas-Fas ligand, perforin/

granzyme B, tumor necrosis factor-alpha, and nitric oxide. I. The incidence of ocular involvement in the acute phase has been reported to be 60%–100%. 1. The spectrum of ocular involvement may range between conjunctiva hyperemia and massive sloughing of the ocular surface epithelium. 2. A final blinding result of SJS/TEN may be from end-stage corneal changes associated with symblepharon formation, ocular xerosis, limbal stem cell deficiency, etc. J. Although the focus of discussion tends to be on ocular and cutaneous complications of SJS/TEN, other systems that may be significantly affected are the respiratory, gastrointestinal/hepatic, oral, otorhinolaryngologic, gynecologic/genitourinary, and renal systems. K. Even after they recover from skin involvement, some SJS/TEN patients continue to suffer with severe ocular complications. 1. Increased levels of inflammatory oxylipins are found on plasma lipid profiling in these patients with severe ocular complications. 2. Oxidized phosphatidylcholines and ether-type diacylglycerols also are found in patients with chronic severe ocular complications, while phosphoglycerolipids decrease. 3. Moreover, decreased levels of ether-type phosphatidylcholines containing arachidonic acid are found in these patients, and are the most specific plasma lipid alterations for them. L. Serum IL-17 levels may have prognostic and diagnostic value in these patients. M. Neutrophilic infiltrate is present in mildly inflamed or clinically quiescent conjunctival mucosa in patients with SJS-TEN where neutrophil numbers inversely correlate with disease duration. N. The following are discussions of SJS and TEN viewed as entities at the extremes of a spectrum. IV. Stevens–Johnson syndrome (SJS) is a severe form of erythema multiforme, starting suddenly with high fever and prostration and showing predominantly a bullous eruption of the skin and mucous membranes, including conjunctiva. The systemic syndrome may lead to death.

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A. Conjunctival microbial flora is increased in SJS so that bacterial cultures are positive in 59% of affected eyes compared to healthy controls. The most common organisms isolated are coagulase-negative staphylococci followed by Corynebacteria species and Staphylococcus aureus. B. Histologic findings 1. In the skin of Stevens–Johnson syndrome, a dense lymphohistiocytic inflammation obscures the dermoepidermal junction and is associated with progressive necrosis of keratinocytes from the basilar to the uppermost portions of the epidermis. 2. In the conjunctiva, epithelial goblet cells and openings of the accessory lacrimal glands may be destroyed, leading to marked drying of the conjunctiva and epidermidalization. 3. Both intraepidermal and subepidermal vesiculation may lead to severe scarring, including symblepharon and entropion. 4. The cellular infiltrate consists largely of lymphocytes, mainly T4 (helper) cells in the dermis and T8 (cytotoxic) cells in the epidermis. 5. Conjunctival scarring may result in the sequestration of conjunctival epithelium that may lead to diverticulum formation and subsequent chronic relapsing conjunctivitis. V. Toxic epidermal necrolysis A. Toxic epidermal necrolysis (TEN) (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). B. TEN (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. C. Staphylococcal scalded-skin syndrome (Ritter’s disease) is not related to erythema multiforme, occurs largely in the newborn and in children younger than 5 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 mortality may be as high as 25%–50%.



D. Histologically, most cases of TEN show a severe degeneration and necrosis of epidermal cells resulting in detachment of the entire epidermis (flaccid bullae). In the acute stage, it is considered a T-cell mediated, type IV hypersensitivity disorder.

Epidermolysis Bullosa I. Epidermolysis bullosa hereditaria (mechanobullous diseases) (EB) includes a group of rare, inherited, noninflammatory, nonimmunologic diseases characterized by the susceptibility of the skin to blister after even mild trauma. The prevalence of EB varies from 8.22 to 60 per 1 million with an incidence of 19.6 to 50 per 1 million live births. A. More than 100 mutations in more than 15 structural genes encoding several structural proteins have been associated with various subtypes of EB. B. Each of the subtypes of inherited EB is defined by its mode of transmission, and a combination of phenotypic, ultrastructural, immunohistochemical and molecular findings. C. Inherited EB is divided into EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome. Fig. 6.17 illustrates the histological level of tissue splitting, for each type of inherited EB and the associated protein. In general, the use of eponyms has decreased for these disorders. 1. EBS (previously referred to as epidermolytic EB) represents all subtypes of EB having mechanical fragility and blistering confined to the epidermis. It is further subdivided into suprabasal and basal subgroups based on the histopathologic suite of cleavage. 2. JEB refers to all subtypes of EB in which blisters develop within the mid portion or junction (lamina lucida) of the skin basement membrane zone (BMZ). a. Underlying the plasma membrane of the basal epithelial cells is a comparatively electron-lucent zone, the lamina lucida, which separates the trilaminar plasma membrane (approximately 8 nm wide) from the medium-dense basement membrane (lamina densa). 3. DEB (previously referred to as dermolytic EB) encompasses all EB subtypes in which blistering occurs within the uppermost dermis, which is beneath the lamina densa of the skin BMZ. It is divided into dominant and recessive subtypes. 4. Kindler syndrome is characterized by the presence of clinical phenotype features of photosensitivity and blistering that arises in multiple levels within and/ or beneath the BMZ, rather than within a discrete plane. Associated skin changes later in life are termed poikiloderma. D. The inheritance for EBS is thought be autosomal dominant and JEB is autosomal recessive. Dystrophic EB can have either an autosomal dominant or autosomal recessive inheritance pattern, and Kindler syndrome has autosomal recessive inheritance.

Lid Manifestations of Systemic Dermatoses or Disease

187

Fig. 6.17  A schematic representation of the epidermis, the skin basement membrane zone, the location of specific proteins pertinent to the pathogenesis of epidermolysis bullosa (EB), and the level in which blisters develop in different EB types. The scheme depicts the cell layers of the epidermis, the basal keratinocytes, and above them the suprabasal keratinocyte layers (spinous and granular layers), which are covered by the horny layer (pink). The epidermis is attached to the dermis by the bilayered basement membrane consisting of lamina lucida and lamina densa (red bar). On the left, the level of blister formation is indicated. In EB simplex (EBS) suprabasal, the blisters form within the middle/upper epidermal layers, depending on which protein is mutated. In EBS basal, the cleavage plain is within the basal keratinocytes. In junctional EB (JEB), the separation takes place within the lamina lucida, and in dystrophic EB (DEB), within the sublamina densa region within the uppermost dermis. In Kindler syndrome (KS), cleavage can occur within the basal keratinocytes, at the level of the lamina lucida or below the lamina densa. On the right, the localizations of the relevant mutated proteins are indicated. Transglutaminase 5 is present in the uppermost cell layers of the epidermis. Plakoglobin and desmoplakin are desmosomal proteins that are panepidermal, compared with plakophilin 1, which is expressed mainly in the suprabasal epidermis. Keratins 5 and 14, plectin, BP230, exophilin 5 and kindlin-1 are found mainly within the basal keratinocytes. Integrin α6β4, integrin α3, and collagen XVII are transmembrane proteins with extracellular domains emanating from the plasma membrane of the basal keratinocytes into the lamina lucida. Laminin 332 is a lamina lucida protein and collagen VII, the major component of the anchoring fibrils, is found in the sublamina densa region. (From Fine et al.: Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification. J Am Acad Dermatol 70(6):1103–1126, 2014. Figure 1. Elsevier.)

II. Ocular complications (especially in recessive epidermolysis bullosa) include loss of eyelashes, obstruction of the lacrimal ducts, and epiphora. A. The incidence of ocular complications varies among EB subtypes. B. They are most severe in the dystrophic recessive and junctional subtypes; however, they also may be significant in Kindler syndrome. C. Late complications include cicatricial ectropion, exposure keratitis, recurrent corneal erosions and ulcers, and even corneal perforation. D. Most children with EB exhibit signs of meibomian gland dysfunction. III. Histologically, according to the different types, blisters can form at various levels in the epidermis. A. The use of immunofluorescence antigen mapping (IFM) and/or targeted next-generation sequencing multi-gene panel in combination can be very helpful, particularly for resolving unusual phenotypes.

1. IFM helps determine the precise level of skin cleavage using monoclonal antibodies to EB-specific basement membrane zone protein.

Contact Dermatitis I. The most common cause of periorbital dermatitis is contact allergy (54%), followed by atopic dermatitis (25%), periorbital rosacea (5%), periorbital psoriasis vulgaris (2%), and allergic conjunctivitis (2%). A. Female gender, atopic skin diathesis, and age over 40 years are risk factors for periorbital dermatitis. II. Contact dermatitis includes a spectrum of reactions including irritant contact dermatitis, allergic contact dermatitis, contact urticaria, phototoxic contact dermatitis, and photoallergic contact dermatitis. A. Irritant contact dermatitis is the most common around the face, and is reflected in erythematous, burning, pruritic skin that may develop microvesiculation and later desquamation.

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1. There is stratum corneum damage without immunologic manifestations. 2. Once damaged, the stratum corneum loses its protective function so that anything subsequently applied may heighten the response and appear, falsely, to generate an allergy to that second product. B. Allergic contact dermatitis is the second most common type of contact dermatitis (Box 6.1). 1. It may manifest in a manner similar to irritant contact dermatitis, although when it is acute it may produce more vesiculation. 2. It is immunologically based and depends upon antigen-processing cells independent of the condition of the protective stratum corneum. C. Contact urticaria may be an immunologic or nonimmunologic reaction that is characterized by the development of a wheal-and-flare response to topically applied products (Table 6.4). 1. Some products may elicit this response by the direct stimulation of histamine without an immunologic response per se. Other products may require prior sensitization.







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.

BOX 6.1  Sources of Allergic Contact

Dermatitis in Skin Care Products and Cosmetics Fragrances Preservatives P-phenylenediamine (permanent hair dyes) Lanolin (moisturizers) Glyceryl thioglycolate (permanent wave solutions) Propylene glycol (moisturizers) Toluenesulfonamide/formaldehyde resin (nail polishes) Sunscreens

(From Draelos ZD: Facial skin care products and cosmetics. Clin Dermatol 32:809–812, 2014. Table 2. Elsevier.)

TABLE 6.4  Contact Urticaria Inducing Skin

Care and Cosmetic Ingredients Nonimmunologic

Immunologic

Acetic acid Alcohols Balsam of Peru Benzoic acid Cinnamic acid Cinnamic aldehyde Formaldehyde Sodium benzoate Sorbic acid

Acrylic monomer Alcohols Ammonia Benzoic acid Benzophenone Diethyltoluamide Formaldehyde Henna Menthol Parabens Polyethylene glycol Polysorbate 60 Salicylic acid Sodium sulfide

(From Draelos ZD: Facial skin care products and cosmetics. Clin Dermatol 32:809–812, 2014. Table 3. Elsevier.)

D. Phototoxic and photoallergic dermatitis are found in light exposed areas. 1. Phototoxic reactions are nonimmunologically based, and result from products that more readily absorb ultraviolet A radiation. 2. Photoallergic dermatitis is less common, and is immunologically based. Therefore, it usually requires repeat exposure. a. Clinically appears as erythema, edema, and vesiculation. E. Eyedrops, particularly atropine and brimonidine, and associated preservatives, may produce contact dermatitis. Additionally, any medication placed on the eye gains access to the systemic circulation following drainage through the lacrimal system, and in this manner, may produce systemic side effects. F. Metals contained in cosmetics are increasingly being recognized as sources for dermatitis and even systemic side effects.

III. 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 (see Fig. 6.18 and Box 6.2, containing the vessel size impacted by the major

Lid Manifestations of Systemic Dermatoses or Disease

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Fig. 6.18  Distribution of vessel involvement by large vessel vasculitis, medium vessel vasculitis, and small vessel vasculitis. Note that there is substantial overlap with respect to arterial involvement, and an important concept is that all 3 major categories of vasculitis can affect any size artery. Large vessel vasculitis affects large arteries more often than other vasculitides. Medium vessel vasculitis predominantly affects medium arteries. Small vessel vasculitis predominantly affects small vessels, but medium arteries and veins may be affected, although immune complex small vessel vasculitis rarely affects arteries. Not shown is variable vessel vasculitis, which can affect any type of vessel, from aorta to veins. The diagram depicts (from left to right) aorta, large artery, medium artery, small artery/arteriole, capillary, venule, and vein. Anti-GBM, antiglomerular basement membrane; ANCA, antineutrophil cytoplasmic antibody. (From Jennette et al.: Revised international Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11, 2013. Figure 2. Wiley.)

BOX 6.2  Names for Vasculitides Adopted by the 2012 International Chapel Hill Consensus

Conference on the Nomenclature of Vasculitides Large Vessel Vasculitis (LVV) Takayasu arteritis (TAK) Giant cell arteritis (GCA) Medium Vessel Vasculitis (MVV) Polyarteritis nodosa (PAN) Kawasaki disease (KD) Small Vessel Vasculitis (SVV) Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (Wegener’s) (GPA) Eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA) Immune complex SVV Anti-glomerular basement membrane (anti-GBM) disease Cryoglobulinemic vasculitis (CV) IgA vasculitis (Henoch–Schönlein) (IgAV) Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) Variable Vessel Vasculitis (VVV) Behçet’s disease (BD) Cogan’s syndrome (CS)

Single-Organ Vasculitis (SOV) Cutaneous leukocytoclastic angiitis Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis Others Vasculitis Associated With Systemic Disease Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis Others Vasculitis Associated With Probable Etiology Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis Others

(From Jennette et al., Revised international Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11, 2013. Table 2. Wiley.)

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CHAPTER 6  Skin and Lacrimal Drainage System

vasculitides and the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides for them, respectively.) A. Periarteritis nodosa is characterized by a necrotizing panarteritis of small- and medium-sized, muscular-type arteries. 1. It most commonly affects men in their fourth to sixth decades. 2. It is not associated with antineutrophil cytoplasmic antibodies (ANCAs). 3. Patients present with systemic symptoms and signs of multisystem involvement, which may include skin lesions, hypertension, renal insufficiency, neurologic dysfunction, and abdominal pain. 4. It can be associated with familial Mediterranean fever. a. Mononeuropathy multiplex occurs in up to 80% of patients. b. Cerebral vasculitis occurs in 5%–10% of patients, and may result in cerebral infarcts. c. Ocular involvement may include retinal vasculitis, ischemic optic neuropathy, scleritis, and orbital inflammation. d. Rheumatoid arthritis, systemic lupus erythematosus, relapsing polychondritis, Wegener’s granulomatosis (granulomatosis with polyangiitis), polyarteritis nodosa, and Churg–Strauss syndrome are the most common systemic diseases associated with corneoscleral disease.





C. The Systemic Lupus International Collaboratory Clinics Classification Criteria for Systemic Lupus Erythematosus lists 17 clinical and immunological criteria useful for making the diagnosis. D. Vasculitis has been reported in up to one-third of patients with SLE. E. SLE affects the eyes in approximately one-third of patients. Table 6.5 lists the ocular manifestations of SLE. 1. There may be immune complex deposition in the basement membrane of endothelial cells of small blood vessels. Involvement usually takes the form of inflammation or thrombosis, such as keratoconjunctivitis sicca, retinopathy, episcleritis, and scleritis. TABLE 6.5  Ocular Involvement in

Systemic Lupus Erythematosus Structure

Clinical Findings

Orbital and external eye disease

Discoid lupus-type rash over the eyelids Panniculitis Orbital masses Periorbital edema Orbital myositis Orbital vasculitis, acute orbital ischemia and infarction Conjunctivitis Dry eye syndrome Recurrent corneal erosions Peripheral corneal infiltrates Peripheral ulcerative keratitis Interstitial keratitis Endotheliitis Keratoconus Scleritis Episcleritis Anterior uveitis Lupus retinopathy (cotton wool spots, intraretinal hemorrhages, and vascular tortuosity) Retinal hard exudates Retinal vasculitis Retinal artery and/or vein occlusion Arteriolar narrowing and arteriovenous crossing changes Macular pigmentary mottling Retinal scarring Macular infarction Central serous chorioretinopathy Optic nerve involvement Optic neuritis Ischemic optic neuropathy Papilledema Central nervous system vasculitis Internuclear ophthalmoplegia Nystagmus Cranial nerve palsies Homonymous hemianopia

Conjunctival involvement Corneal involvement

Rarely it may present as bilateral optic neuropathy. Sclera and episclera



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: transmural infiltrate characterized by predominantly neutrophils, but also eosinophils and lymphocytes, infiltrates the necrotic areas, which frequently represent fibrinoid necrosis. Small caliber vessels such as glomerular and pulmonary capillaries are not affected. 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. Systemic lupus erythematosus (SLE) can have protean manifestations, and the diagnosis is based on a combination of clinical and laboratory findings, serology, and histology of affected organs. A. It affects more than 300,000 individuals in the United States, and millions of people worldwide. B. Over 100 genetic loci have been associated with SLE. Additionally, epigenetic biomarkers hold promise for diagnosing and monitoring lupus diseases and the risk of organ damage.

Uveal involvement Retinal involvement

Choroidal involvement Neuro-ophthalmic findings

(From Shoughy & Tabbara, Ocular findings in systemic lupus erythematosus. Saudi J Ophthalmol 30:117–121, 2016. Table 1. Elsevier.)

Lid Manifestations of Systemic Dermatoses or Disease













2. Other findings may include conjunctivitis, peripheral ulcerative keratitis, anterior uveitis, choroidopathy, orbital inflammation and optic neuropathy. 3. Drusen-like deposits have been reported in young adults with SLE. 4. Antiphospholipid syndrome may accompany SLE. It has resulted in bilateral retinal arterial and venous occlusions with vasculitis. 5. Bilateral concurrent superior ophthalmic vein occlusions have been reported in SLE. F. SLE includes cutaneous lesions in 72%–85% of patients, and they can develop at any stage of the disease irrespective of disease activity. 1. They represent the first sign of the disease in 23%–28% of patients. 2. Cutaneous lupus erythematosus (CLE) manifestations are divided into lupus-nonspecific and specific lesions. a. Among the nonspecific lesions are periungual telangiectasia, livedo racemosa, thrombophlebitis, Raynaud’s phenomenon, acral occlusive vasculopathy, leukocytoclastic vasculitis (palpebral purpura or urticarial vasculitis), papular mucinosis, calcinosis cutis, nonscarring alopecia, and erythema multiforme. b. SLE-specific lesions constitute the subtypes of cutaneous SLE. c. They are divided into three categories based upon clinical features of the various lesions, histopathological findings in skin biopsy specimens, and laboratory findings. 1) The categories of cutaneous lupus erythematosus are acute (ACLE), subacute (SCLE), and chronic (CCLE). 2) Discoid lupus erythematosus, subacute cutaneous lupus erythematosus, lupus erythematosus panniculitis, and lupus erythematosus tumidus all fall within the subtype of CLE. 3) Only discoid lupus erythematosus will be discussed more specifically in this chapter. a) Discoid lupus erythematosus may be limited to the skin or there may be systemic involvement. b) Discoid lupus erythematosus (DLE) is the most common subtype of cutaneous lupus. c) It is classified as a chronic (CCLE) form of cutaneous involvement. d) It represents 80% of all cutaneous lupus cases. e) It may present as eyelid edema an erythema. f) There is an increased risk of squamous cell carcinoma in longstanding DLE lesions, and these tumors have a higher rate of recurrence, metastasis, and death. g) Transition from the chronic discoid type to the systemic type occurs infrequently. h) Histology is similar in the various CLE subtypes, and overall is not useful in

191

differentiating among them. Nevertheless, features that have been cited as favoring a diagnosis of chronic discoid lupus erythematosus (CDLE), which is DLE without systemic disease, over other CLE subtypes are the presence of hyperkeratosis, basement membrane thickening, follicular damage, leukocytic infiltration and involvement in CDLE; however, they have been questioned as to their validity for this purpose. 4) In general, dermatologic changes in CLE are: (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. 5) IgG antibodies are critical for the development of CLE associated with SLE. a) Tissue specific antibodies such as anti-RPLP0 and anti-Galactin-3 antibodies, rather than conventional lupus-related autoantibodies, are responsible for lupus skin damage. b) The cutaneous inflammatory infiltrate in CDLE are dominated by the T-helper (Th1), but not Th17 cells in contrast to the findings in SLE. c) Keratinocytes undergo apoptosis and may produce proinflammatory cytokines in both SLE and in CDLE. d) Location of lesions, characteristic features of damage, and absence of Ro/SSA antibody may be most effective in differentiating CDLE from other cutaneous lupus erythematosus subtypes. IV. Scleroderma (Fig. 6.19) has been described as a clinically heterogeneous connective tissue disorder characterized by fibroblast dysfunction, small-vessel vasculopathy, and autoantibody production. A. It exists in three forms: (1) a more benign circumscribed form, limited cutaneous systemic sclerosis (lcSSc), also known as morphea and characterized by CREST syndrome, which is characterized by Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasis. It is predominantly restricted to the skin and subcutaneous tissue, and almost never progresses or transforms to the systemic form; (2) a systemic form, diffuse cutaneous systemic sclerosis (dcSSc) or (progressive systemic sclerosis or scleroderma), which may prove fatal; and (3) SSC without skin involvement.

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A

B

Fig. 6.19  Scleroderma. A, Typical changes in face and hands of patient who has scleroderma. B, Cotton-wool spots seen in fundus of person with advanced scleroderma. C, Dermis thickened and subcutaneous tissue mostly replaced by collagen. Atrophic sweat glands appear trapped in midst of collagen bundles.

C









B. Morphea occurs equally in adults and children, and is more common in women. It presents with systemic symptoms of fatigue, myalgia, arthralgia and skin induration that worsens over time. Eventually, there is loss of adnexal structures. 1. Some have referred to this as limited cutaneous systemic sclerosis because there also may be pulmonary hypertension as a late finding and primary biliary cirrhosis. 2. Antinuclear antibodies, recognized as chromosomal centromere proteins, are present in 50% of patients. C. Systemic involvement in dcSSc may include skin, gastrointestinal tract, lungs, kidneys, skeletal muscle and pericardium. D. The characteristic lesion is a sclerotic plaque with an ivory-colored center and appearing bound-down when palpated. E. Ocular findings include pseudoptosis secondary to swollen lids, ectropion, madarosis, hyposecretion of tears with trophic changes in the cornea and conjunctiva (Sjögren’s syndrome), ocular muscle palsies, temporal arteritis, unilateral glaucoma, exophthalmos, thinner corneas, posterior subcapsular cataract, anterior uveitis, neural retinal cotton-wool patches, signs of hypertensive retinopathy, choroidal impairment, macular thinning, defects of the retinal pigment epithelium near the macula, central serous choroidopathy, retinal artery occlusion, and fluorescein leaks of thickened retinal capillaries.





F. 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.

Lid Manifestations of Systemic Dermatoses or Disease

















G. Increased levels of inflammatory proteins are found in the serum of patients with SSC who have not yet shown evidence of fibrotic disease. H. Genomic and genetic studies of patients with SSC and family members provide evidence that chromosomal breakage is a main feature in these families. 1. HLA studies find that HLA-DRB1, HLA-DQA1, HLA-DQB1 and HLA-DPB1 are identified most frequently. 2. The most frequent gene associations are with STAT4, CD247, and IRF5. 3. CXCL4 and adiponectin are two serologic biomarkers that have demonstrated prognostic utility in systemic sclerosis. 4. Antibody profiling is becoming important in systemic sclerosis. A relationship has been established between RNAP and cancer diagnosis in a subset of patients. I. Parry–Romberg syndrome (PRS) (progressive hemifacial atrophy, idiopathic hemifacial atrophy, or hemiatrophia faciei [progressive]), and linear scleroderma en coup de sabre (LSCS). (For an excellent review of PRS, the reader is referred to the article by Bucher et al. in the bibliography for this chapter). 1. Both are considered forms of linear morphea, which is a type of localized scleroderma, characterized by thickening and hardening of the skin from increased collagen production. 2. Both have a similar clinicopathologic appearance. a. Up to 28% of patients with LSCS have features of PRS such as progressive hemifacial atrophy or histopathologic similarities on skin biopsy. It has been noted that conversion from LACS to PRS may occur. b. Deeper tissues of the head and neck usually are not involved in LSCS. 3. PRS is an acquired disorder accompanied by slowly progressive atrophy of facial subcutaneous tissues, muscles, osteocartilaginous structures, and possibly with cerebral involvement. Table 6.6 lists the periocular findings in PRS. a. It usually is unilateral. b. Ocular manifestations occur in 10%–35% of patients and may involve the contralateral eye. Table 6.7 lists the ocular manifestations of PRS. c. Neuro-ophthalmic findings may include abnormalities of the pupil, including anisocoria; optic nerves, including papillitis and neuroretinitis; and extraocular muscles. d. Systemic manifestations are protean and may include neurologic, dermatologic, cardiac, endocrine, infectious, orthodontic, and maxillofacial abnormalities. 4. LSCS usually involves the frontoparietal scalp and/ or the paramedian forehead. The disorder gets its name from the fact that is resembles a scar secondary to a wound from a sword.

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TABLE 6.6  Periocular Findings in

Parry–Romberg Syndrome Periocular Structure

Periocular Manifestations

Skin Eyebrows/lashes

Hyperpigmentation/depigmentation Alopecia Asymmetry Retraction Lagophthalmos Atrophy Pseudoptosis Pseudocoloboma Enophthalmos due to retroorbital fat atrophy Enophthalmos due to bone atrophy Alterations of orbital wall and retroocular structures Orbital tumors Deviation toward the affected side of hemifacial atrophy

Eyelid

Orbit

Mouth and nose

(From Bucher et al.: Ophthalmological manifestations of ParryRomberg syndrome. Surv Ophthalmol 61:693–701, 2016. Table 1. Elsevier.)

TABLE 6.7  Ocular Manifestations in

Parry–Romberg Syndrome Ocular Structure

Ocular Manifestations

Conjunctiva Cornea

Palpebral pigmentation Band keratopathy Exposure keratopathy Decreased corneal nerves Reduced corneal sensation Flourlike stromal deposits Primary corneal endothelial failure Discrete, irregularly round, glassy precipitates Refractive changes Photophobia Spontaneous scleral melting Anterior uveitis Iris atrophy Iris crystalline deposits Fuchs heterochromic iridocyclitis Panuveitis Inflammation Hypotony/phthisis (Bilateral) vitritis Retinal vasculitis Retinal telangiectasia Retinal pigment epithelial changes Retinal edema Retinitis pigmentosa Retinal detachment Coats disease Sectional chorioretinal atrophy Central retinal artery occlusion Choroidal/retinal folding and hyperopia due to phthisis

Sclera Iris/Uvea

Ciliary body Vitreous Retina

(From Bucher et al.: Ophthalmological manifestations of ParryRomberg syndrome. Surv Ophthalmol 61:693–701, 2016. Table 2. Elsevier.)

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a. LSCS is the most common form of scleroderma in childhood. b. Ninety percent of affected children present between 2 and 14 years of age. c. The eye and adnexa may be involved. It frequently is associated with other internal organ involvement, particularly of the central nervous system. 1) In one multicenter study in children, the eyelids, eyelashes or lacrimal glands are the most frequently involved ocular or periocular structures (41.7%). 2) Anterior segment inflammation was present in 29.2%. 3) Other ocular findings included pupillary mydriasis associated with CNS abnormalities, enophthalmos, partial iris atrophy, stellate neuroretinitis, retinal telangiectasia, strabismus, pseudopapilledema, and refractive errors. 4) Systemic manifestations included epilepsy, peripheral neuropathy, pseudotumor cerebri, arthritis, aortic insufficiency, abnormal pulmonary function tests, and Raynaud’s phenomenon. 5) Patients with ocular involvement had a higher incidence of internal organ involvement, particularly of the CNS, than those lacking ocular findings (45.8% vs 21.6%). 6) ANA was positive in 50% of patients with LSCS. 7) Other studies have found episcleral vascular anomaly, retinal telangiectasia, and exudative retinal detachment with a Coats-like response in association with LSCS.

Granulomatous Vasculitis







Table 6.8 lists the revised classification of vasculitis based on histopathologic feature of granuloma formation. I. Granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis) A. Grouped with eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg–Strauss syndrome) as an ANCA-associated granulomatous vasculitis involving small vessels.



1. Another ANCA-positive vasculitis, microscopic polyangiitis (MPA) is characterized by nongranulomatous inflammation. 2. They are termed the “ANCA-associated vasculitides.” 3. Other forms of non-ANCA-associated vasculitis, typically, are characterized by the presence of immune complex deposition (lupus vasculitis, Henoch– Schönlein purpura, and Goodpasture’s disease). B. Classic form: characterized by generalized small-vessel vasculitis, necrotizing granulomas, focal necrotizing glomerulonephritis, and vasculitis of the upper and lower respiratory tract. 1. Otorhinologic manifestations are found in 90% of patients, and it is the most commonly involved organ system. 2. Pulmonary involvement is present in 85% of patients, but may be asymptomatic. 3. Rapidly progressive glomerulonephritis is a presenting finding in 20% of patients; however, up to 80% of patients ultimately develop it. 4. It may have the unique finding of strawberry gingival enlargement. 5. Typical presentation is a persistent inflammatory nasal and sinus disease associated with systemic symptoms of fever, malaise, and migratory arthritis. 6. Serum antineutrophil cytoplasmic antibodies (ANCAs) are a sensitive and rather specific marker for GPA. 7. The ANCAs are divided into perinuclear or p-ANCA, or cytoplasmic or c-ANCA. a. C-ANCA pattern with leukocyte proteinase 3 (PR3) positivity is found in 90% of GPA patients with active disease. b. Most MPA patients have p-ANCA with positive myeloperoxidase (MPO). 8. In both the classic and limited forms, most of the ocular findings can occur. 9. Ocular involvement, most commonly orbital, occurs in up to 50%, and neurologic involvement in up to 54% of cases. C. Ocular findings include dry eyes, nasolacrimal obstruction, blepharitis, conjunctivitis, scleritis or episcleritis,

TABLE 6.8  Classification of Vasculitis Based on Histopathologic Feature of Granuloma

Formation

Large-Vessel Vasculitis Granulomatous inflammation Nongranulomatous inflammation

Medium-Vessel Vasculitis

Small-Vessel Vasculitis

Classic polyarteritis nodosa Kawasaki disease

Granulomatosis with polyangiitis* Eosinophilic granulomatosis with polyangiitis† Microscopic polyangiitis IgA vasculitis‡ Essential cryoglobulinemic vasculitis Cutaneous leucocytoclastic vasculitis

Temporal arteritis Takayasu arteritis

*Previously known as Wegener’s granulomatosis. † Previously known as Churg–Strauss syndrome. ‡ Previously known as Henoch–Schönlein purpura. (From Sharma et al.: Granulomatous vasculitis. Dermatol Clin 33:475–487, 2015. Table 1. Elsevier.)

Lid Manifestations of Systemic Dermatoses or Disease

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. D. Histologically, the classic triad of necrotizing vasculitis (granulomatous and disseminated small-vessel), tissue necrosis, and granulomatous inflammation are characteristic. 1. The vasculitis can be seen in three forms: a. Microvasculitis or capillaritis—infiltration and destruction of capillaries, venules, and arterioles by neutrophils. b. Granulomatous vasculitis (most characteristic)— granulomatous vasculitis involving small or medium-sized arteries and veins. c. Necrotizing vasculitis involving small or mediumsized arteries and veins but not associated with granulomatous inflammation. 2. Extravascular granulomatosis is a major factor differentiating MPA from GPS. In EGPA, the extravascular lesions usually are not associated with necrotizing granulomatous inflammation. E. It is associated with HLA-DRB1*04, DPB1*0401, PRTN3 (A546G poly), and AAT polymorphisms (SERPINA1). F. Among the precipitating factors are believed to be environmental, drugs, and infectious triggers. II. Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly allergic granulomatosis, allergic vasculitis, or Churg– Strauss syndrome) involves the same-size arteries as periarteritis, but differs in having more prominent respiratory symptoms including asthma, pulmonary infiltrates, systemic and local eosinophilia, intravascular and extravascular granulomatous lesions, and often cutaneous and subcutaneous nodules and petechial lesions. It has been suggested that the associated asthma resembles a nonallergic eosinophilic asthma phenotype. A. The three disease phases are prodromal, eosinophilic, and vasculitic. 1. The main features of the prodromal stage are asthma and allergic rhinitis with or without polyposis. Upper airway involvement is milder than in GPA. 2. The second stage is marked by peripheral and tissue eosinophilia. 3. The vasculitic phase includes multiple system involvement including nerves, heart, lungs, gastrointestinal tract, and kidneys. Peripheral nerves and skin are most frequently involved. B. The most common skin lesions are purpura and nodules most commonly on the limbs and scalp. C. It is considered a Th2-mediated disease. B cells and humoral response also may contribute to its pathobiology. D. ANCA-positivity is present only in about 40% of patients. E. Histopathologic evaluation in the early phase demonstrates extravascular tissue infiltration in any organ.

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1. The vasculitic phase is characterized by inflammation involving small to medium-sized vessel walls. 2. The vasculitis involves fibrinoid necrosis and infiltration of the vessel walls by eosinophils. F. There may a limited form of the disease that is confined to single organs. 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) (also see discussion in Chapter 14) A. NK cells are a distinct non-T, non-B lineage of lymphocytes that mediate major histocompatibility complexunrestricted 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+ 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% 5-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. 1. Survival is particularly brief. H. Gamma-delta 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.

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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 6.9) A. Includes 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. E. Pseudocarcinomatous hyperplasia has been reported in association with lymphomatous papulosis. F. A benign atypical intravascular CD30+ T-cell proliferation has been reported in association with inflammation or trauma, and must be distinguished from intravascular T-cell lymphoma.



G. Lymphoid papulosis can be malignant histologically, but clinically benign and characterized by rhythmic paradoxical eruptions of erythematous papules. 1. There is a 10%–20% risk for developing lymphoma or a nonlymphoid tumor. 2. It has been divided into 4 histological types with type A resembling Hodgkin’s disease, type B resembling mycosis fungoides, type C resembling anaplastic large-cell lymphoma, and type D simulating aggressive epidermotropic CD8+ T-cell lymphoma. 3. A recent variant, type E, is an angiocentric and angiodestructive infiltrate of small- to medium-sized atypical lymphocytes that are CD30+ and frequently express CD8. 4. Type C has been reported to involve the eyelid in a teenage girl in whom the dermis contained a heavy superficial and deep infiltrate that included numerous large atypical lymphoid cells.

TABLE 6.9  Clinical and Pathologic Findings in CD30+ Lymphoid Proliferations Demographics Symptoms/clinical findings

Histology

Contrasts in immunohistochemistry

Treatment

Prognosis

LyP

cALCL

Systemic ALCL

Median age: 45 years • Recurrent papular/nodular lesions on trunk/extremities ± ulceration with spontaneous regression after 4–6 weeks • Hyper- or hypopigmented scar may remain 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

Median age: 60 years • ≥1 lesion that is >2 cm in diameter ± erythema and ulceration • No extracutaneous involvement

Males <30 years • Stage III or IV with B symptoms • Noncontiguous lymphadenopathy • 40% with extranodal disease

• 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–Sternberglike cells, donut cells, and hallmark cells may be seen • Six histologic variants; neutrophil-rich variant may be mistaken for LyP, type A CD30+ CLA expression minimal EMA +

CD30+ CD30+ CLA + CLA expression variable EMA − 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 • Usually none • Resection ± irradiation • Low-dose MTX for skin-restricted • PUV A or low- dose MTX has been used for aggressive disease disease • Chemotherapy for extracutaneous disease • Benign • Less aggressive than systemic ALCL • Increased risk for progressing to • Better survival rate than for systemic mycosis fungoides, Hodgkin’s ALCL; 5-year survival rate of 90% lymphoma, or ALCL • Spontaneous regression occurs in ≥40%

• Local radiation with combination chemotherapy

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

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 et al.: Spectrum of CD30+ lymphoid proliferations in the eyelid: lymphomatoid papulosis, cutaneous anaplastic large cell lymphoma, and anaplastic large cell lymphoma. Ophthalmology 117:343–351, 2010.)

Lid Manifestations of Systemic Dermatoses or Disease



a. The nuclei were pleomorphic and bizarre with multinucleated forms. b. The infiltrate was both perivascular and interstitial, and included moderated numbers of small- to medium-sized mildly atypical lymphoid cells. c. The large pleomorphic cells were positive for CD30 and CD45, and were ALK negative. T-cell receptor analysis suggested T-cell receptor gene rearrangement. III. Mycosis fungoides (also see discussion in Chapter 14) A. Most common type of cutaneous T-cell lymphoma but rarely involves 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.



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A. The lesions appear as bilateral, soft, yellowish plaques most commonly at the inner aspects of the upper and lower lids. B. Although usually localized, extensive lesions have been reported. C. There is a 4.4% prevalence. D. Xanthelasma is the most common cutaneous 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). E. Other xanthomatous lesions that may occur in the periorbital area are Langerhans’ cell histiocytosis, diffuse normolipemic xanthoma, and non-Langerhans’ cell histiocytoses (papular xanthoma, juvenile xanthogranuloma, xanthoma disseminatum, adult-onset xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, necrobiotic xanthogranuloma, Erdheim–Chester disease, Rosai–Dorfman disease, and reticulohistiocytosis). 1. Malignant melanoma involving the eyelid has masqueraded as a xanthogranuloma and included histopathologic findings of an inflammatory infiltrate of lymphocytes, histiocytes, and giant cells with Touton giant cell features. The associated malignancy was consistent with melanoma.





Xanthelasma I. Xanthelasma (Fig. 6.20) most commonly occurs in middleaged or elderly women; however, female predominance has not been found universally.

A

B

C

D Fig. 6.20  Xanthelasma. A, Characteristic clinical appearance of xanthelasmas that involve inner aspect of each upper lid. B, Lipid-laden foam cells are present in dermis and tend to cluster around blood vessels. C, High magnification of foam cells clustered around blood vessels. D, Oil red-O stain for fat demonstrates dermal lipid positivity (red globules).

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F. It may occur in primary hypercholesterolemia or with nonfamilial serum cholesterol elevation. It frequently is associated with abnormal serum lipid levels. 1. It is a risk factor for myocardial infarction, ischemic heart disease, severe atherosclerosis, and death independent of other cardiovascular risk factors, such as plasma cholesterol and triglyceride concentrations. 2. The presence of a tendency for increased cardio-ankle vascular index in asymptomatic patients with xanthelasma has been seen to indicate increased arterial stiffness in these individuals, which is a noninvasive marker for atherosclerosis. 3. Compounding risk factors for cardiovascular disease frequently have been noted in patients with xanthelasma. The risk factors in one study included nicotine addiction (39.3%), dyslipidemia (60%), hypertension (37.7%), prehypertension (8.77%), diabetes mellitus (18.03%), and prediabetes (26.3%). 4. It has been proposed that alterations in serum levels of apolipoprotein A1 (decrease) and B (increase) may predispose to the deposition of lipids in the skin as is found in xanthelasma, and may contribute to the systemic deposition of lipids thereby facilitating the development of atherosclerosis. Compared to control individuals, patients with xanthelasmas had an accompanying increase in carotid intima media thickness compatible with atherosclerosis. 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, that xanthelasma is a marker of dyslipidemia, and that patients who have xanthelasma should undergo a full lipid profile to identify those who are at an increased risk for cardiovascular disease.

II. After initial surgical excision, the recurrence rate is slightly less than half. 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. Lid lesions resembling xanthelasma occur in Erdheim– Chester disease, which is an idiopathic, widespread, multifocal, granulomatous disorder characterized by cholesterol-containing foam cells infiltrating viscera and bones, including the orbit, and sometimes bilateral xanthelasmas. It is one of the Langerhans’ cell histiocytoses and can be viewed as an inflammatory myeloid clonal disorder based on the presence of activating mutations along the mitogen activated protein kinase–extracellular signal regulated kinase (MAPK-ERK) pathway with the

most notable variant being a valine to a glutamic acid substitution at amino acid 600 in the B-rapidly accelerated fibrosarcoma protein (BRAFV600E). When the orbit is involved, there tends to be bilateral involvement. Histologically, the lesions show broad sheets of lipid-filled xanthoma cells and scattered foci of chronic inflammatory cells, mainly lymphocytes and plasma cells, along with significant fibrosis. Touton giant cells may be found.

IV. Histologically, lipid-containing foam cells are found in the superficial dermis. The cells cluster around blood vessels and may even involve their walls. A. In one study of 1541 excised lesions on which histopathology had been performed, it represented 7.6% of lesions. B. A comparative histopathologic and immunohistochemical study between blepharoplasty specimens and excised xanthelasmas demonstrated more intense chronic lymphocytic infiltrate, more intense CD3+ T-cell and CD163+ histiocytic infiltrate, and increased cyclooxygenase and inducible nitric oxide synthetase expressing cells in the xanthelasma specimens compared to the blepharoplasty tissue. The authors concluded that these findings resembled the inflammatory milieu similar to that found in the early stages of atherosclerosis. V. Periorbital hyperpigmentation has been noted in 82.4% of patients with xanthelasma. This finding occurred predominantly in women (86.2%) compared to men (13.8%). Unfortunately there was no control population to exclude an ethnic or other basis for these findings. VI. Injected foreign material, such as poly-L-lactic acid, used as tissue fillers may cause a reaction that clinically resembles a xanthelasma, but histopathologically is a paraffinoma.

Necrobiotic Xanthogranuloma I. Necrobiotic xanthogranuloma is rare, with only approximately 100 cases having been reported, and over 80% were in the periorbital region. A. Cutaneous involvement is universal, with the periorbital region a site of predilection. B. The typical lesion is an indurated papule, nodule, or plaque that is violaceous to red-orange, often with a central ulceration or atrophy. II. The most characteristic abnormal laboratory finding is a paraproteinemia. A. It is associated with monoclonal gammopathy. 1. IgG-kappa type is most common (65%), followed by IgG lambda (35%). 2. Other associations have been reported. 3. Multiple myeloma has been diagnosed in a patient with a 20 year history of indolent bilateral xanthogranulomas of the eyelids. III. Systemic findings include hepatomegaly, splenomegaly, lymphadenopathy, arthralgia or arthritis, pulmonary disease, and hypertension.

Lid Manifestations of Systemic Dermatoses or Disease

IV. It tends to involve the periocular skin or anterior orbit, and may produce secondary exophthalmos, ptosis or motility disturbance. A. Other ocular findings include conjunctivitis, episcleritis, keratitis, and anterior uveitis. B. Orbital involvement can include the lacrimal gland, extraocular muscles, or other orbital tissue. V. Histologically, it is a type of non-Langerhans’ cell histiocytosis, which exhibits granulomatous masses separated by broad bands of hyaline necrobiosis. Giant cells are of the foreign-body type and often the Touton type. The lesions most closely resemble necrobiosis lipoidica diabeticorum, but they may also be confused with juvenile xanthogranuloma, granuloma annulare, erythema induratum, atypical sarcoidosis, Erdheim–Chester disease, Rothman–Makai panniculitis, foreign-body granulomas, various xanthomas, nodular tenosynovitis, and the extraarticular lesions of proliferative synovitis.

Juvenile Xanthogranuloma (JXG) I. JXG constitutes a family of non-Langerhans’ cell histiocytoses that include papular xanthoma, benign cephalic histiocytosis, xanthoma disseminatum, progressive nodular histiocytosis, spindle cell xanthogranuloma, and generalized eruptive histiocytosis. See Box 6.3 for a list of these lesions. II. JXG is the most common non-Langerhans’ cell histiocytosis. A. Nevertheless, JXG involving the eyelid is uncommon. It is found in only 10% of cases of ocular JXG.

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B. The ocular manifestations can be quite variable, but spontaneous hyphema is a common presenting sign of iris involvement. III. Almost 50% of JXG occurs in the first year of life. An unusual presentation of JXG has been as a papillary eyelid lesion in an adult.

IV. It is believed to result from disordered macrophage response to a nonspecific injury. V. Histologically it is characterized by the presence of benign mononuclear cells, Touton giant cells, and an inflammatory infiltrate of T lymphocytes and eosinophils. A. The mononuclear cells usually are CD68 positive with CD14 membrane staining. They are said to express CD163 at the cell surface and stain strongly for Factor XIIIa and Fascin. B. S100 usually is negative but can be weak. CD1a and CD207 (Langerin), however, are negative. C. Giant cells usually are CD68 positive in a zonal pattern and S100 is negative, but they are strongly positive for Fascin and variable for XIIIa. D. There is a “mitotically active” form of JXG, but it lacks nuclear atypia or atypical mitoses. E. Touton giant cells are not necessary for the diagnosis of JXG, and they tend to be reduced in number or absent in extracutaneous lesions compared to subcutaneous JXG. They also are found rarely in early lesions. Table 6.10 lists the types of multinucleated giant cell types in nonepithelial skin tumors.

BOX 6.3  Non-Langerhans’ Cell

Histiocytosis

Cutaneous Non-LCH Juvenile xanthogranuloma (JXG) family: Benign cephalic histiocytosis Juvenile xanthogranuloma Generalized eruptive histiocytoma Adult xanthogranuloma Progressive nodular histiocytosis Non-JXG cutaneous histiocytosis: Solitary reticulohistiocytoma Non-LCH dendritic cell histiocytosis Indeterminate histiocytosis Cutaneous With a Major Systemic Component JXG family: Xanthoma disseminatum Non-JXG family: Multicentric reticulohistiocytoma Systemic Non-LCH JXG family: Erdheim–Chester disease Non-JXG family: Sinus histiocytosis with massive lymphadenopathy (From Ranganathan S: Histiocytic proliferations. Semin Diagn Pathol 33:396–409, 2016. Table 4. Elsevier.)

TABLE 6.10  Multinucleated Giant Cell

Types in Nonepithelial Skin Tumors Cell Type

Cutaneous Nonepithelial Tumors

Touton

Juvenile xanthogranuloma Necrobiotic xanthogranuloma Xanthomas Dermatofibroma Reticulohistiocytoma Multicentric reticulohistiocytosis Xanthogranuloma (adult) Soft-tissue giant cell tumor Plexiform fibrohistiocytic tumor Atypical fibroxanthoma Dermatofibroma Giant cell fibroblastoma Pleomorphic lipoma Multinucleate cell angiohistiocytoma Giant cell collagenoma Juvenile xanthogranuloma Necrobiotic xanthogranuloma Dermatofibroma Reticulohistiocytoma

Glassy

Osteoclast-like

Floret-like

Foreign body

(From Gomez-Mateo & Monteagudo: Nonepithelial skin tumors with multinucleated giant cells. Semin Diagn Pathol 30:58–72, 2013. Table 1. Elsevier.)

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VI. The presence of neurofibromatosis type 1 and JXG in the same patient indicates the need for monitoring for the possible development of juvenile myelomonocytic leukemia. VII. Cutaneous JXG accompanies ocular involvement in only 10% of cases. See also Chapter 9.

Amyloidosis Rarely, nodular cutaneous amyloid tumors of the eyelid may occur in the absence of systemic amyloidosis. See also Chapter 7.

Atrophic Papulosis (Köhlmeier–Degos Disease) (Benign and Malignant) I. The syndrome is a rare syndrome of unknown cause characterized by the diffuse eruption of asymptomatic skin lesions with porcelain-white atrophy centers. A. The lesions have a telangiectatic rim. B. They are most commonly found on the trunk and proximal extremities, but can involve the face, scalp and genitals. C. Their occurrence marks the onset of the disease. D. The skin lesions are characteristic of the disorder; however, similar lesions also may occur in primary antiphospholipid syndrome caused by lupus, and can coexist with dermatomyositis. E. They also have occurred in association with lupus without antiphospholipid syndrome. F. Moreover, skin pathology in lupus can be similar to it. II. Systemic involvement involves infarcts of the gastrointestinal system, central nervous system and other organs and in one study of 39 patients occurred in 29% of individuals. A. Family history for the disorder was positive in 9% of patients. B. Mortality was 73% in patients with systemic involvement (5-year survival, 54.5%), and 73% of the individuals who died developed intestinal perforation. C. None of the patients lacking systemic disease died. D. Thus, the cutaneous form of the disease is benign; however, the mortality in the malignant form, which has systemic manifestations, is high. III. Involves small blood vessels. A. There is endothelial dysfunction and immune dysregulation in the pathogenesis of the disorder. 1. It also has been suggested that complement activation and enhanced endothelial cell apoptosis contribute to the pathobiology of the malignant form of the disease, although large vessel proliferative intimal changes were not thought to be secondary to complement activation. IV. Ocular lesions include porcelain-white lid lesions; a characteristic white, avascular thickened plaque of the conjunctiva; telangiectasis of conjunctival blood vessels and microaneurysms; strabismus; posterior subcapsular cataract, choroidal lesions such as peripheral choroiditis, small plaques of atrophic choroiditis, gray avascular areas, and discrete loss of choroidal pigment and peripheral retinal pigment epithelium; visual field changes; and intermittent diplopia

and papilledema, associated with progressive central nervous system involvement. V. Histologically, there is a wedge-shaped area of degenerate dermal connective tissue with an arteriole at the base that displays a hyalinized wall and/or luminal thrombosis. A. Capillaries are occluded by endothelial proliferation and swelling; the end-arterioles show endothelial proliferation, swelling, and fibrinoid necrosis involving only the intima; arterial involvement is greater than venous; thrombosis may occur secondary to endothelial changes; and no significant inflammatory cellular response is noted. B. It has been proposed that these changes can resolve with time.

Calcinosis Cutis I. Calcinosis cutis has five forms: A. Metastatic calcinosis cutis, or calcium deposition secondary to either hypercalcemia (e.g., with parathyroid neoplasm, hypervitaminosis D, and extensive destruction of bone by metastatic carcinoma) or hyperphosphatemia (e.g., with chronic renal disease and secondary hyperparathyroidism). 1. Deposition occurs after the calcium phosphate product exceeds 70. 2. Most commonly seen in chronic renal failure. 3. Also seen in hypervitaminosis D, hyperparathyroidism, sarcoidosis, milk-alkali syndrome and malignancies. B. Dystrophic calcinosis cutis (i.e., deposition in previously damaged tissue) 1. Most common variety. 2. Normal laboratory values for calcium and phosphorus. 3. Secondary to an underlying disease, such as systemic sclerosis, dermatomyositis, mixed connective tissue disease or lupus that produces the site that will be the focus for the calcification. a. Found in 25%–40% of patients with limited systemic sclerosis (CREST) after 10 years. b. Develops in 30% of adults, and 70% of children and adolescents with dermatomyositis. 1) Most often involves pressure areas such as elbows, knees, buttocks, and fingers. 2) May be related to intensity of inflammation and the local production of TNFα. c. Related to release of phosphate-binding protein by dying cells. d. Also related to chronic inflammation. e. Anti-nuclear matrix protein 2 (Anti-NXP2) autoantibodies are associated with calcinosis in pediatric dermatomyositis. C. Idiopathic is not associated with previous tissue injury or abnormal laboratory studies (Fig. 6.21). 1. Includes tumoral calcinosis, subepidermal calcified nodules, and scrotal calcinosis.

Lid Manifestations of Systemic Dermatoses or Disease

A

201

B

Fig. 6.21  Subepidermal calcified nodule. A, Clinical photo of subcutaneous nodule resembling a cystic lesion at the medial canthus. B, Photomicrograph demonstrating acanthotic papillomatous epidermis overlying calcific deposits. (Courtesy of Dr. Tatyana Milman.)

2. Tumoral calcinosis also is seen in familial tumoral calcinosis, which is an autosomal recessive disorder characterized by extraosseous deposition of calciumphosphate crystals in soft tissues and peri-articular spaces. a. All mutations are related to the stability or signaling efficacy of fibroblast growth factor 23 (FGF23), which is a protein involved in phosphate homeostasis. 3. Acral milia-like idiopathic calcinosis cutis usually occurs in children with Down syndrome. a. It usually is found on the hands and feet, and the lesions usually resolve by adulthood. b. They are described as multiple, round, firm white papules resembling milia, and may have an associated erythematous halo. c. The lesions may spontaneously perforate and discharge their calcium contents. d. There may be associated palpebral and perilesional syringomas. D. Iatrogenic is caused by exogenous administration of a calcium- or phosphate-containing substance that then results in the precipitation of calcium salts. E. Calciphylaxis is a rare disease characterized by calcification of small- and medium-sized blood vessels in the dermis and subcutis with intimal fibrosis, and associated, in particular, with renal failure and dialysis. It has a high mortality rate. 1. It occurs in 4% of patients on chronic hemodialysis. 2. Calciphylaxis also may be seen in POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, which is associated with plasma cell dyscrasias and upregulation of vascular endothelial growth factor (VEGF). a. Skin changes include hyperpigmentation, acrocyanosis, hemangioma, telangiectasia, hypertrichosis, and skin thickening. II. Histologically, forms A and B show large deposits of calcium (appears as granules that are black with von Kossa’s stain)

in the subcutaneous tissue and small, granular deposits in the dermis, whereas form C shows deposits of irregular granules and globules in the upper dermis and can show a foreign-body reaction.

Lipoid Proteinosis (Urbach–Wiethe Disease, Hyalinosis Cutis et Mucosae) I. Lipoid proteinosis (Fig. 6.22) is a rare condition of the lids and mucous membranes that has an autosomal-recessive inheritance pattern. A. The disorder maps to 1q21, and is caused by mutations in the extracellular matrix protein 1 (ECM1) gene. B. The main function of the ECM1 protein appears to be that of a biological glue that maintains dermal homeostasis, and regulates basement membrane and interstitial collagen fibril micro assembly. II. Presents in early childhood. Earliest sign may be hoarseness or a weak cry in infancy. III. Two stages that may overlap: A. First stage lasts until late teens, and lesions are pustules, bullae, and hemorrhagic crusts of the skin mouth and throat. Skin lesions resolve with “ice-pick” acneiform scar. B. Second stage marked by increased deposits in the dermis, and the skin becomes thickened, yellowed, and waxy. 1. Papules and plaques develop progressively over several years on the face, scalp, neck, and extremities. The scalp may show alopecia areata. 2. “Woody” changes develop in the tongue with changes affecting other mucosal surfaces. 3. Characteristic changes are the development of beaded papules on the eyelid margins (moniliform blepharosis), which are a diagnostic finding. a. They are multiple, waxy, pearly nodules, 2 to 3 mm in diameter, cover the lid margins linearly along the roots of the cilia. b. They appear after the age of 4 years.

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A

B

C

D Fig. 6.22  Lipoid proteinosis. A, Multiple, waxy, pearly nodules cover the lid margins. B, Histologic section shows papillomatosis with collections of amorphous material in dermis. Material is positive for lipid (C, Sudan IV stain) and is also periodic acid–Schiff-positive (D). (Case presented by Dr. J Duke at the Eastern Ophthalmic Pathology Society meeting, 1966.)

IV. Other ocular findings A. Prominent corneal nerves are present independent of age, and are more apparent in patients with more severe genetic mutations. 1. Confocal microscopy of the cornea can be helpful in corneal nerve examination; however, it failed to demonstrate abnormalities other than prominent corneal nerves in one study. 2. Corneal sensation is normal. B. There may be focal degeneration of the macula, and drusen formation in Bruch’s membrane in 30%–50% of patients. C. Other ocular abnormalities reported in association with lipoid proteinosis have involved glaucoma, cataract, cornea, uveitis, iris, conjunctiva, ocular surface, lacrimal gland, and nasolacrimal duct obstruction. D. Keratoconus has been reported. V. Whitish plaques are found on mucous membranes. VI. Characteristic calcifications are seen on radiologic examination. These include oval symmetrical intracranial calcification of the hippocampal gyri in 50% of cases. Neurologic and psychiatric manifestations can include memory impairment, paranoia, rage attacks, mental retardation, and temporal lobe epilepsy.

VII. Histologically, there is papillomatosis of the epidermis with hyperkeratosis and acanthosis. There is dermal thickening and deposition of extracellular, homogeneous, hyaline material in the upper dermis. A. The material is PAS-positive without inflammation. B. There is deposition of pale, eosinophilic, hyaline material in the walls of small blood vessels. C. Electron microscopy shows large masses of an extracellular, finely granular, amorphous material without a fibrillar structure. D. It has been suggested that there is overproduction of basement membrane collagens (type IV and V) by blood vessel endothelial cells, and underproduction of fibrous collagens (type I and II).

Idiopathic Hemochromatosis I. Brown pigmentation of the lid margin, conjunctiva, cornea, and around the disc margin (see Chapter 1). II. Histologically, the pigmentation is caused by an increased melanin content of the epidermis, especially the basal layer. A. The peripapillary pigmentation may result from small amounts of iron in the peripapillary retinal pigment epithelium.

Cysts, Pseudoneoplasms, and Neoplasms



B. Intraocular deposition of iron is most prominent in the nonpigmented ciliary epithelium, but may also be found in the sclera, corneal epithelium, and peripapillary retinal pigment epithelium.

Relapsing Febrile Nodular Nonsuppurative Panniculitis (Weber–Christian Disease) I. The condition, which is of unknown cause, occurs most often in middle-aged and elderly women. It is characterized by malaise and fever and by the appearance of crops of tender nodules and papules in the subcutaneous fat, usually on the trunk and extremities. II. Ocular findings include necrotic eyelid and subconjunctival nodules and, rarely, ocular proptosis, anterior uveitis, and macular hemorrhage. Uveitis, which may be granulomatous, and retinitis have been reported. III. Histologically, three stages can be seen. A. An early, rapid phase shows fat necrosis and an acute inflammatory infiltrate of neutrophils, lymphocytes, and histiocytes. B. A second stage shows a granulomatous inflammation with lipid-filled macrophages, epithelioid cells, and foreign-body giant cells. C. A third stage of fibrosis may result clinically in depression of the overlying skin.

Pigmentation

keratinocytes in these patients have abundant mature melanosomes compared to controls. III. Periocular orange pigmentation may be a manifestation of carotenoderma, which represents the deposition of carotene mainly in the stratum corneum of the skin, and may reflect food consumption rich in oranges and carrots.

CYSTS, PSEUDONEOPLASMS, AND NEOPLASMS In a study of 5504 eyelid skin tumors, the 5 most frequent subtypes were squamous cell papilloma (26%), seborrheic keratosis (21%), melanocytic nevus (20%), hidrocystoma (8%), and xanthoma/xanthelasma (6%). Basal cell carcinoma was the most frequent malignant tumor (86%), followed by squamous cell carcinoma (7%) and sebaceous carcinoma (3%).

Benign Cystic Lesions I. Epidermoid (Fig. 6.23) and dermoid (see Figs. 14.12 and 14.13) cysts are congenital lesions that tend to occur at the outer upper portion of the upper lid. II. Epidermal inclusion cysts (see Fig. 6.23) appear identical histologically to congenital epidermoid cysts; the former are not congenital, but are caused by traumatic dermal implantation of epidermis or are follicular cysts of the hair follicle infundibulum that result from occlusion of its orifice, sometimes the result of trauma.

I. Argyrosis A. Periocular and eyelid skin can be involved in argyrosis, resulting in the typical grayish discoloration.

Milia are identical histologically to epidermal inclusion cysts; they differ only in size, milia being the smaller. They may represent retention cysts, caused by the occlusion of a pilosebaceous follicle or of sweat pores, may represent benign keratinizing tumors, or they may have a dual origin. Multiple epidermal inclusion cysts, especially of the face and scalp, may occur in Gardner’s syndrome.

Chronic use of eyelash tint has been an unusual cause for the disorder.

II. Prostaglandin treatment for glaucoma or for eyelash enhancement may result in increased melanin pigmentation of the periocular skin without melanocyte proliferation. The

A

203

B Fig. 6.23  Epidermoid cyst. A, Large epidermoid cyst present on outer third of left upper lid. Note xanthelasma in corner of left upper lid. B, The cyst has no dermal appendages in its wall and is lined by stratified squamous epithelium that desquamates keratin into its lumen. Histologically, an epidermoid cyst is identical to an epithelial inclusion cyst, but it differs from a dermoid cyst in that the latter has epidermal appendages in its wall.

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Histologically, the cyst is lined by epithelial cells simulating surface epithelium. The cavity contains loose, laminated keratin. III. Sebaceous (pilar, trichilemmal) cysts are caused by obstruction of the glands of Zeis, of the meibomian glands, or of the isthmus portion of the hair follicle, from which keratinization analogous to the outer root sheath of the hair or trichilemma arises. Histologically, the cyst is lined by epithelial cells that possess no clearly visible intercellular bridges. A. The peripheral layer of cells shows a palisade arrangement, and the cells closest to the cavity are swollen without distinct cell borders. B. The cyst cavity contains an amorphous eosinophilic material. The epithelial cells lining the sebaceous cyst are different from the typical cells lining an epidermal inclusion cyst, in which the cells are stratified squamous epithelium. The cystic contents of the sebaceous cyst are different from the horny (keratinous) material filling the epidermal inclusion cyst. “Old” sebaceous cysts, however, may show stratified squamous epithelial metaplasia of the lining, resulting in keratinous material filling the cyst and producing a picture identical to an epidermal inclusion cyst, unless a microscopic section accidentally passes through the occluded pore of the sebaceous cyst.

IV. Comedo (blackhead, primary lesion of acne vulgaris) presents clinically as follicular papules and pustules. A. The comedo occludes the sebaceous glands of the pilosebaceous follicle, which may undergo atrophy. B. Histologically, the comedo results from intrafollicular orthokeratosis that leads to a cystic collection of sebum and keratin. C. With rupture of the cyst wall, sebum and keratin are released, causing a foreign-body giant cell granulomatous reaction. Bacteria, especially Propionibacterium acnes, may be found. D. Eventually, epithelium grows downward and encapsulates the inflammatory infiltrate. E. The lesion heals by fibrosis. V. Steatocystoma A. Steatocystoma may occur as a solitary cyst (simplex) or as multiple cysts (multiplex), the latter often inherited as an autosomal-dominant trait. B. The small, firm cysts, which exude an oily or creamy fluid when punctured, are derived from cystic dilatation of the sebaceous duct that empties into the hair follicle. 1. A ruptured canthal steatocystoma simplex has presented as a lacrimal sac mass. C. Histologically, a thick, eosinophilic cuticle covers the several layers of epithelial cells lining the cyst wall. Sebaceous lobules are present either within or close to the cyst wall.

VI. Calcifying epithelioma of Malherbe (pilomatrixoma; Fig. 6.24) A. Calcifying epithelioma of Malherbe is a cyst derived from the hair matrix that forms the hair. B. It can occur at any age, but most appear in the first two decades of life; it presents as a solitary tumor, firm, deepseated, and covered by normal skin. Nevertheless, it is frequently misdiagnosed when occurring in young adults. If superficial, it produces a blue-red discoloration. 1. It is reported to be the most common adnexal skin tumor in young patients. a. A review of 16 cases found that 75% of patients were younger than 13 years. A similarly young demographic for the lesion has been reported by others. 2. It has been reported to have a rapid onset following blunt trauma to the eyebrow. 3. The lesion has simulated a chalazion. Conversely, an inflammatory tumor of the eyelid that probably was secondary to IgG4-related sclerosing disease has mimicked pilomatrixoma. 4. Presentation as a rapidly enlarging recurrent mass in an elderly, 97-year-old patient has been reported. A rapidly enlarging lesion in a 5-year-old child clinically raised the suspicion of rhabdomyosarcoma. Periorbital pilomatrixoma has occurred in a 3-yearold girl with a history of bilateral retinoblastoma. C. Histologically, the tumor is sharply demarcated and composed of basophilic and shadow cells. 1. Basophilic cells closely resemble the basaloid cells of a basal cell carcinoma (dark basophilic nucleus surrounded by scant basophilic cytoplasm). 2. Shadow cells stain faintly eosinophilic, have distinct cell borders, and instead of nuclei show central, unstained regions where the nuclei should be. In older tumors, basophilic cells may have disappeared completely so that only shadow cells remain. 3. The stroma may show areas of keratinization, fibrosis, calcification, foreign-body granuloma, and ossification. 4. In one study, only 18.75% of lesions were diagnosed correctly clinically. Follicular hybrid cyst of the tarsus, which had features of pilomatricoma and steatocystoma, has been reported to perforate the palpebral surface of the conjunctiva.

D. Pilomatrix carcinoma may develop from malignant transformation of a benign pilomatricoma or may arise de novo. VII. Hidrocystoma (Figs. 6.25 and 6.26) A. Cysts resulting from occlusion of the eccrine or apocrine duct are referred to as hidrocystomas. 1. When multiple, these can be associated with Goltz– Gorlin syndrome (GGS) or Schopf–Schulz–Passarge syndrome (SSPS).

Cysts, Pseudoneoplasms, and Neoplasms

205

B A

Fig. 6.24  Calcifying epithelioma of Malherbe (pilomatricoma). A, Clinical photo of lesion involving the lateral aspect of the right lower eyelid. B, Low-magnification photomicrograph demonstrating position of lesion relative to the skin surface and light areas of necrosis containing shadow cells and dark basophilic cells. C, High magnification of pale shadow cells on left and dark basophilic cells on right. (A and B, Courtesy of Dr. Morton Smith; C, courtesy of Armed Forces Institute of Pathology, Washington, DC, accession number 984935.)

C







a. GGS usually is sporadic; however, it also may be X-linked dominant. It is characterized by mesoectodermal defects that may involve the skin, eyes, or teeth. 1) The skin may display linear or reticulated atrophic hypo- or hyperpigmented lesions, papillomas and periocular multiple hidrocystomas. 2) There may be microcephaly; midfacial hypoplasia; malformed ears; microphthalmia; papillomas of the lip, tongue, anus, and axilla; skeletal abnormalities; and mental retardation. b. SSPS is an autosomal form of ectodermal dysplasia. It is characterized by hypodontia, hypoplastic nails, hypotrichosis, palmoplantar keratosis, cysts of the eyelid margins, and multiple periocular apocrine hidrocystomas. c. Multiple eccrine hidrocystomas also are found in association with Graves’ disease. 2. Apocrine hidrocystomas usually occur in adults as solitary (sometimes multiple) lesions, often with a blue tint, and are usually located in the skin near the eyes. 3. A congenital massive orbital lesion has resulted in “extrusion” of the globe. Other large lesions have caused eyelid ptosis.





4. The extrusion of lipofuscin pigment into an apocrinerich cyst can result in a pigmented hidrocystoma containing brown-black contents. B. Eccrine hidrocystomas may be solitary or multiple, and clinically are indistinguishable from apocrine hidrocystomas. 1. They can become very large and may even cause eyelid ptosis. Large orbital lesions can impact eyelid function. 2. The lesion may arise on the tarsal plate. 3. Based on immunohistochemical studies, apocrine hidrocystomas probably predominate over eccrine hidrocystomas in the eyelids. C. Histology 1. The apocrine hidrocystoma, which is derived from the apocrine sweat glands of Moll, is an irregularly shaped cyst, and has an outer myoepithelium layer and an inner (luminal) layer of columnar epithelium, showing apical decapitation secretion. 2. The eccrine hidrocystoma, which is derived from the eccrine sweat glands, is more rounded and shows a flattened wall that contains one or two layers of cuboidal epithelium and sometimes contains papillary projections into the lumen of the cysts (mean age at diagnosis is 59 years; 71% of lesions are single;

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A

B

Fig. 6.25  Ductal cyst, probably apocrine, caused by clogged sweat duct, may take many forms. A, Ductal cyst noted near the outer margin of the right lower lid. B, Multiloculated large ductal cyst appears empty. C, The cyst is lined by a double layer of epithelium.

C

A

B

Fig. 6.26  Eccrine hidrocystoma. A, Clinical appearance of lesion. B, Histologic section shows a flattened wall lined by one or two layers of cuboidal epithelium and containing papillary projections into the lumen of the cysts. C, Increased magnification of papillary projections.

C

Cysts, Pseudoneoplasms, and Neoplasms

and 87% are located near but not on the eyelid margin).

epidermis showing a normal polarity but some degree of acanthosis and hyperkeratosis, along with variable parakeratosis and elongation of rete pegs.

Benign Tumors of the Surface Epithelium I. Papilloma (Figs. 6.27 and 6.28) A. Papilloma is an upward proliferation of skin resulting in an elevated irregular lesion with an undulating surface. B. Six conditions show this type of proliferation as a predominant feature: (1) nonspecific papilloma (most common); (2) nevus verrucosus (epidermal cell nevus; Jadassohn); (3) acanthosis nigricans; (4) verruca vulgaris (see earlier under subsection Viral Diseases); (5) seborrheic keratosis; and (6) actinic keratosis (see later under section Precancerous Tumors of the Surface Epithelium). C. Histologically, a papilloma is characterized by finger-like projections or fronds of papillary dermis covered by

The dermal component may have a prominent vascular element. Usually, histologic examination of a papillomatous lesion indicates which of the different papillomatous conditions is involved.



A

B

C

D

D. Nonspecific papilloma (see Fig. 6.28) 1. Nonspecific papilloma, a polyp of the skin, is usually further subdivided into a broad-based and a narrowbased type. The broad-based type is called a sessile papilloma and the narrow-based type is called a pedunculated papilloma, a fibroepithelial papilloma, acrochordon, or simply a skin tag.

Fig. 6.27  Differences between benign and malignant skin lesions. A, An elevated skin lesion sitting as a “button” on the skin surface. This is characteristic of benign papillomatous lesions. When such lesions appear red histologically under low magnification, they show acanthosis, as in actinic keratosis. B, Lesions structurally similar to A but that appear blue under low magnification are caused by proliferation of basal cells, as in seborrheic keratosis. C, An elevated lesion that invades the underlying skin is characteristic of a malignancy. Invasive lesions that appear red under low magnification are caused by proliferation of the squamous layer (acanthosis), as in squamous cell carcinoma. D, A lesion structurally similar to C but that appears blue under low magnification represents proliferation of basal cells, as seen in basal cell carcinoma.

A

207

B Fig. 6.28  Fibroepithelial papilloma. A, Clinical appearance of two skin tags (fibroepithelial papillomas) of left upper lid. B, Fibroepithelial papilloma consists of a narrow-based (to the right) papilloma whose fibrovascular core and finger-like projections are covered by acanthotic, orthokeratotic (hyperkeratotic) epithelium.

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2. Histologically, finger-like projections of papillary dermis are covered by normal-thickness epithelium showing elongation of rete ridges and orthokeratosis. E. Nevus verrucosus (epidermal cell nevus; Jadassohn) 1. Nevus verrucosus consists of a single lesion present at birth or appearing early in life. 2. Histologically, the lesion consists of closely set, papillomatous, orthokeratotic papules, marked acanthosis, and elongation of rete pegs. F. Acanthosis nigricans Acanthosis nigricans exists in five types, all showing papillomatous and verrucous brownish patches predominantly in the axillae, on the dorsum of fingers, on the neck, or in the genital and submammary regions.







1. Hereditary (benign) type: not associated with an internal adenocarcinoma, other syndromes, or endocrinopathy; benign type: associated with insulin resistance, endocrine disorders, and other disorders such as Crouzon’s disease; pseudoacanthosis nigricans: a reversible condition related to obesity; drug-induced type; and adult (malignant) type: associated with an internal adenocarcinoma, most commonly of the stomach. 2. The benign form associated with obesity, insulin resistance, diabetes mellitus, and drug use is relatively common and comprises 80% of cases of the disorder. a. In particular, facial involvement may be a morphologic marker for metabolic syndrome. b. It is the most frequent manifestation of pediatric obesity, and occurs in 66% of overweight adolescents and in 56% to 92% of children and adolescents with type 2 diabetes mellitus. c. There is a particularly high incidence in Native American children associated with obesity and diabetes. 3. When associated with malignancy, it is observed in 58% of patients before the tumor is diagnosed. The malignant form is associated with tumor products, tumor necrosis factors, and insulin-like activity. 4. Histologically, the first four are identical and show marked orthokeratosis and papillomatosis and mild acanthosis and hyperpigmentation. a. The fifth has additional malignant cytologic changes. b. The dark color is said to be more related to hyperkeratosis than to the presence of melanin. G. Seborrheic keratosis results from an intraepidermal proliferation of benign basal cells (basal cell acanthoma; see Fig. 6.27; Fig. 6.29). 1. Seborrheic keratosis increases in size and number with increasing age and is most common in the elderly. 2. The lesions tend to be sharply defined, brownish, softly lobulated papules or plaques with a rough, almost warty surface.

sk s

A

B Fig. 6.29  Seborrheic keratosis. A, The “greasy” elevated lesion is present in the middle nasal portion of the left lower lid. Biopsy showed this to be a seborrheic keratosis (sk). The smaller lesion just inferior and nasal to the seborrheic keratosis proved to be a syringoma (s; see Fig. 6.42). Another seborrheic keratosis is present on the side of the nose. B, Histologic section shows a papillomatous lesion that lies above the skin surface and is blue. The lesion contains proliferated basaloid cells and keratin-filled cysts.

3. Rarely, squamous cell carcinoma may arise in seborrheic keratosis. 4. Seborrheic keratosis may be pigmented either secondary to environmental debris deposited on the lesion’s heavily keratinized surface, or from actual melanin produced by melanocytes, which can contribute to the lesion being mistaken for a malignant melanoma. 5. In one report, the lesion comprised 12.6% of 4521 specimens received for histopathologic examination. Of course, this number represents only those lesions about which the patient or surgeon were concerned, and in no way represents the actual prevalence of the lesion in the population. 6. Histologically, the lesion has a papillomatous configuration and an upward acanthosis so that it sits as a “button” on the surface of the skin and contains a proliferation of cells closely resembling normal basal cells, called basaloid cells. The histologic appearance of a seborrheic keratosis is variable. The lesion frequently contains cystic accumulations of horny (keratinous) material. Six

Cysts, Pseudoneoplasms, and Neoplasms subtypes are recognized: acanthotic, hyperkeratotic, reticulated (adenoid), clonal, irritated (IFK; see later), and melanoacanthoma. All show acanthosis, orthokeratosis, and papillomatosis. Some may show an epithelial thickening (acanthotic) or a peculiar adenoid pattern in which the epithelium proliferates in the dermis in narrow, interconnecting cords or tracts (reticulated). It may be deeply pigmented (melanoacanthoma) and even confused clinically with a malignant melanoma.



7. Inverted follicular keratosis (IFK) (irritated seborrheic keratosis, basosquamous cell epidermal tumor, basosquamous cell acanthoma; Fig. 6.30) resembles a seborrheic keratosis but has an additional squamous element. a. IFK is a benign epithelial skin lesion found most frequently on the face in middle-aged or older people, typically presenting as an asymptomatic, pink to flesh-colored, small papule, rarely pigmented. Rarely, IFK may recur rapidly after excision. Re-excision cures the lesion.





c. Most IFKs are identical to irritated seborrheic keratoses, whereas others may be forms of verruca vulgaris or a reactive phenomenon related to pseudoepitheliomatous hyperplasia (see later). d. Histologically, IFK is similar to a seborrheic keratosis or verruca vulgaris, but with the addition of basaloid cells around whorls of squamous epithelium forming squamous eddies. II. Pseudoepitheliomatous hyperplasia (invasive acanthosis, invasive acanthoma, carcinomatoid hyperplasia; Fig. 6.31) consists of a benign proliferation of the epidermis simulating an epithelial neoplasm. A. It is seen frequently at the edge of burns or ulcers, near neoplasms such as basal cell carcinoma, malignant melanoma, or granular cell tumor, around areas of chronic inflammation such as blastomycosis, scrofuloderma, and gumma, or in lesions such as keratoacanthoma and perhaps IFK. B. Histologically, the usual type of pseudoepitheliomatous hyperplasia, no matter what the associated lesion, if any, consists of irregular invasion of the dermis by squamous cells that may show mitotic figures, but do not show dyskeratosis or atypia, and frequent infiltration of the squamous proliferations by leukocytes, mainly neutrophils.

b. It usually shows a papillomatous configuration, exists as a solitary lesion, and may exhibit rapid growth.

A

Although an inflammatory infiltrate is frequently seen under or around a squamous cell carcinoma, the

B

Fig. 6.30  Inverted follicular keratosis. A, Clinical appearance of lesion in the middle of the right lower lid. B, Histologic section shows a papillomatous lesion above the skin surface composed mainly of acanthotic epithelium. C, Increased magnification shows separation or acantholysis of individual squamous cells that surround the characteristic squamous eddies.

C

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A

B

Fig. 6.31  Pseudoepitheliomatous hyperplasia. A, Clinical appearance. B, Histologic section shows marked acanthosis, mild orthokeratosis, and inflammation characteristically present in dermis and epidermis. C, High magnification shows polymorphonuclear leukocytes in dermis and epidermis.

C

A

B Fig. 6.32  Keratoacanthoma. A, This patient had a six-week history of a rapidly enlarging lesion. Note the umbilicated central area. B, Histologic section shows that the lesion is above the surface epithelium and has a cup-shaped configuration and a central keratin core. The base of the acanthotic epithelium is blunted (rather than invasive) at the junction of the dermis.

inflammatory cells almost never infiltrate the neoplastic cells directly. If inflammatory cells admixed with squamous cells are seen, especially if the inflammatory cells are neutrophils, a reactive lesion such as pseudoepitheliomatous hyperplasia should be considered.

III. Keratoacanthoma (Fig. 6.32) A. Keratoacanthoma (KA) may be a type of pseudoepitheliomatous hyperplasia, although most dermatopathologists believe it is a type of low-grade squamous cell





carcinoma of hair follicle origin, and use the classification, squamous cell carcinoma, keratoacanthoma type, to reflect this conclusion. B. Classically, it is described as consisting of a solitary lesion (occasionally grouped lesions) that develops on exposed (usually hairy) areas of skin in middle-aged or elderly people, grows rapidly for 2 to 6 weeks, shows a raised, smooth edge and an umbilicated, crusted center, and then involutes in a few months to a year, leaving a depressed scar. C. It has been reported in infants in association with xeroderma pigmentosa.

Cysts, Pseudoneoplasms, and Neoplasms



a keratoacanthoma from squamous cell carcinoma, and indeed, some keratoacanthomas show areas of undisputed squamous cell carcinoma differentiation. The superficially invasive variant of keratoacanthoma, called invasive keratoacanthoma, may not involute spontaneously and probably represents a more aggressive form of squamous cell carcinoma.

D. Multiple KAs are rare, and may be sporadic or familial. 1. Generalized eruptive keratoacanthomas of Grzybowski occur on sun-exposed areas, and may cause a characteristic masked face from periocular involvement (sign of Zorro, which is named for a Johnston McCulley fictional character). Ectropion may be a consequence. a. Sudden onset of hundreds to thousands of lesions. b. Lesions are intensely pruritic. c. May be associated with visceral neoplasms.



IV. Warty dyskeratoma A. It presents primarily on the scalp, face, or neck as an umbilicated, keratotic papule, resembling a keratoacanthoma. B. Histologically, a cup-shaped invagination is filled with keratin and acantholytic, dyskeratotic cells. Villi of dermal papillae lined by a single layer of basal cells project into the base of the crater. The histopathology is identical to Darier’s disease. C. May be related to a localized error in epithelial maturation and cohesiveness similar to Darier’s disease, which is an ATP2A2 mutation (Fig. 6.33).

Rarely, keratoacanthoma can occur on the conjunctiva.



E. Histologically, keratoacanthoma is characterized by its dome- or cup-shaped configuration with elevated wall and central keratin mass seen under low magnification, and by acanthosis with normal polarity seen under high magnification. The deep edges of the tumor appear wide and blunt, rather than infiltrative.

Corps ronds (i.e., dyskeratotic cells containing pyknotic nuclei, surrounded by a clear halo, present in the granular layer at the entrance to the invagination) are reminiscent of Darier’s disease.

In the past, the tumor has been confused with “aggressive” squamous cell carcinoma. The typical noninvasive, elevated cup shape with a large central keratin core, as seen under low-power light microscopy, along with the benign cytology and wide and blunt deep edges seen under high-power light microscopy, should lead to the proper diagnosis of keratoacanthoma. If, however, only a small piece of tissue (e.g., a partial biopsy) is available for examination, it may be difficult or impossible to differentiate

A

211

V. Large cell acanthoma A. Large cell acanthoma appears as a slightly keratotic, solitary lesion, usually smaller than 1 cm, and has a predilection for the face and neck, followed by the upper

B Fig. 6.33  Warty dyskeratoma (WD) of the right lower eyelid in a 60-year-old woman presenting as a slowly growing papule. A, Benign and malignant epithelial neoplasms were considered in the clinical differential. B, Histologically, the lesion was an endo-exophytic epithelial neoplasm composed of uniform keratinocytes with zones of acantholysis and dyskeratosis with corps ronds and corps grains. The cause of WD is unknown. The presence of acantholysis and dyskeratosis suggests a localized error in epithelial maturation and cohesiveness akin to that seen in Darier’s disease (ATP2A2 mutation). Attempts to define human papillomavirus as pathogenic have been uniformly unsuccessful. (From Phelps et al.: Warty dyskeratoma of the eyelid. Ophthalmology 122(7):1282, 2015. Elsevier.)

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II. Xeroderma pigmentosum—see section Congenital Abnormalities earlier in this chapter. III. Radiation dermatosis A. The chronic effects include atrophy of epidermis, dermal appendages, and noncapillary blood vessels; dilatation or telangiectasis of capillaries; and frequently hyperpigmentation. B. Squamous cell carcinoma (most common), basal cell carcinoma, or mesenchymal sarcomas such as fibrosarcoma may develop years after skin irradiations (e.g., after radiation for retinoblastoma). IV. Actinic keratosis (senile keratosis; solar keratosis) occurs as multiple lesions on areas of skin exposed to sun (Fig. 6.34; see Fig. 6.27). A. Fair-skinned people are prone to development of multiple neoplasms, including solar keratosis and basal and squamous cell carcinomas. B. The lesions tend to be minimally elevated, slightly scaly, and flesh-colored to pink, but present as a papilloma or as a projecting cutaneous horn.

extremities. It has not been documented to progress to squamous carcinoma. B. Histologically, it is a benign hyperpigmented epidermal lesion showing a moderately acanthotic epidermis that contains sharply circumscribed, uniformly hyperplastic keratinocytes, a wavy, orthokeratotic, and parakeratotic granular cell layer, and sometimes a papillomatosis. Polyploidy may be present. C. Some have considered it a variant of solar lentigo with cellular hypertrophy. 1. It also has been viewed as a subtype of seborrheic keratosis or a human papillomavirus-induced acanthoma. 2. Other conclusions also have been reported.





Dysplastic enlarged keratinocytes and an increased number of Civatte bodies (necrotic keratinocytes) may be found.

VI. Benign keratosis consists of a benign proliferation of epidermal cells, usually acanthotic in form, which does not fit into any known classification.

A cutaneous horn (cornu cutaneum) is a descriptive clinical term. The lesion has many causes, e.g. actinic keratosis, verruca vulgaris, seborrheic keratosis, IFK, squamous cell carcinoma (uncommonly), and even sebaceous gland carcinoma (rarely). Approximately 77% are associated with benign lesions at the base, 15% are premalignant, and 8% are associated with

Precancerous Tumors of the Surface Epithelium I. Leukoplakia—this is a clinical term that describes a white plaque but gives no information about the underlying cause or prognosis; the term should not be used in histopathology.

A

B Fig. 6.34  Actinic keratosis. A, The clinical appearance of a lesion involving the left upper lid. B, Histologic section shows a papillomatous lesion that is above the skin surface, appears red, and has marked hyperkeratosis and acanthosis. C, Although the squamous layer of the skin is increased in thickness (acanthosis) and the basal layer shows atypical cells, the normal polarity of the epidermis is preserved.

C

Cysts, Pseudoneoplasms, and Neoplasms malignant lesions. In another study of 13 cases involving the eyelid, the incidence of malignancy was 23%. Therefore, an underlying malignancy must be considered in evaluating all lesions that present as a cutaneous horn. The most common histopathologic benign diagnosis is seborrheic keratosis; premalignant, actinic keratosis; and malignant, squamous cell carcinoma.



C. Histologically, actinic keratosis is characterized by focal to confluent parakeratosis overlying an epidermis of variable thickness. Both cellular atypia and mitotic figures appear in the deeper epidermal layers, which may form buds extending into the superficial dermis. The underlying dermis usually shows actinic elastosis and an inflammatory reaction mainly of lymphocytes and some plasma cells.

and tends to be only locally invasive, almost never metastasizing. The overproduction of Sonic Hedgehog, the ligand for PTC (tumor suppressor gene PATCHED) mimics loss of PTC function and induces basal cell carcinomas in mice; it may play a role in human tumorigenesis. Ptch-1 mutations have been suggested to contribute to the development of BCC.





Actinic keratosis may become quite pigmented and then mimic, both clinically and histopathologically, a primary melanocytic tumor. Actinic keratosis also may resemble squamous cell carcinoma or Bowen’s disease. It differs from the former in not being invasive and from the latter in not showing total replacement (loss of polarity) of the epidermis by atypical cells. Squamous cell carcinoma infrequently and basal cell carcinoma rarely may arise from actinic keratosis.



Cancerous Tumors of the Surface Epithelium Handheld in vivo reflectance confocal microscopy holds promise for supplementing traditional clinical methods in the evaluation of lesions of the eyelids and conjunctiva. In general, the strongest evidence from published reports regarding the treatment of malignant eyelid tumors supports complete surgical removal using histologic controls for verifying tumor-free surgical margins.

I. Basal cell carcinoma (BCC) (Figs. 6.35 and 6.36; see Fig. 6.27) A. Over 500,000 new cases of skin cancer occur each year in the United States; at least 75% are basal cell carcinoma. Approximately 16% are located on the eyelids, most commonly on the lower eyelids. B. BCC is, by far, the most common malignant tumor of the eyelids and accounts for 85%–90% of all malignant epithelial eyelid tumors in non-Asian countries. 1. It occurs most frequently on the lower eyelid, followed by the inner canthus, the upper eyelid, and then the lateral canthus. 2. It occurs most commonly in fair-skinned people on skin areas exposed to ultraviolet radiation (i.e., sunexposed areas). C. The neoplasm has no sex predilection, is found most often in whites, mainly in the seventh decade of life,

213





D. The clinical appearance varies greatly, but most present as a painless, shiny, waxy, indurated, firm, pearly nodule with a rolled border and fine telangiectases. 1. Ulceration and pigmentation may occur. 2. Approximately 5% of BCCs are pigmented. a. The pigment usually varies in density and distribution rather than being uniform. b. Histopathologic examination reveals melanophages within the stroma accompanied by basaloid cell melanization. 3. Rarely, metastases may occur. E. Histologically and clinically, the tumor has considerable variation, but it can be grouped into four major types: nodular, superficial, micronodular, and infiltrative. 1. In the periocular areas, the relative frequency of these subtypes is nodular (65.7%), infiltrative (17.5%), superficial (12.6%), and micronodular (4.2%). 2. Infiltrative and micronodular tumors have a significantly increased risk of recurrence and morbidity. 3. An additional and aggressive variety of BCC of particular significance on the face is morpheaform BCC, which also will be discussed. 4. It is particularly important to report evidence of perineural invasion, lymphovascular invasion, and level of invasion on histopathologic examination for high rick BCC. 5. Infiltrative and superficial subtypes of BCC occur more frequently in the periocular region, and at lower latitudes compared with on the head and neck, and at higher latitudes. 6. Moreover, although individual subtypes of BCC are delineated here, a mixed histology may occur in up to 38.5% of tumors with nodular mixed with infiltrative, or nodular with superficial being particularly common in the periocular region. F. Most common varieties of BCC 1. Nodular (garden-variety) type occurs most commonly. a. Small, moderate-sized, or large groups or nests of cells resembling basal cells show peripheral palisading. 1) Cells in the nests contain large, oval, or elongated nuclei and little cytoplasm, may be pleomorphic and atypical but tend to be fairly uniform, and may contain mitotic figures. 2) The abnormal cells show continuity with the basal layer of surface epithelium.

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b ds d

A

B

pp

ds C

D Fig. 6.35  Basal cell carcinoma. A, This firm, indurated painless lesion had been present and growing for approximately eight months. B, Excisional biopsy shows epithelial proliferation arising from the basal layer of the epidermis (b, basal cell carcinoma). The proliferated cells appear blue and are present in nests of different sizes. Note the sharp demarcation of the pale-pink area of stroma supporting the neoplastic cells from the underlying (normal) dark-pink dermis (d, relatively normal dermis). This stromal change, called desmoplasia (ds, desmoplastic stroma), is characteristic of neoplastic lesions. Compare with the benign lesions in Figs. 6.27–6.30, where the dermis does not show such a change. C, The nests are composed of atypical basal cells and show peripheral palisading (pp). Mitotic figures are present. Again, note the pseudosarcomatous change (desmoplasia) (ds, desmoplastic stroma) of the surrounding supporting stroma, which is light-pink and contains proliferating fibroblasts. D, Higher magnification illustrates characteristic features of basal cell carcinoma, including atypical cells and separation artifact between nests of cells and desmoplastic surrounding connective tissue. (A, Courtesy of Dr. HC Scheie; D, courtesy of Dr. Morton Smith.)



b. The neoplasm may show surface ulceration, large areas of necrosis resulting in a cystic structure, areas of glandular formation, and squamous or sebaceous differentiation (nodular basal cell carcinoma variants include keratotic, adenoidal, and pigmented).

(i.e., the fibroblasts become large, numerous, and often bizarre, and the mesenchymal tissue becomes mucinous, loose, and “juicy” in appearance). The stromal desmoplastic reaction is typical of the basal cell neoplasm and helps differentiate the tumor from the similarly appearing adenoid cystic carcinoma (see Fig. 14.37), which frequently has an amorphous, relatively acellular surrounding stroma.

Some basal cell carcinomas may be heavily pigmented from melanin deposition and clinically simulate malignant melanomas.



c. The surrounding and intervening invaded dermis undergoes a characteristic pseudosarcomatous (resembling a sarcoma) change called desmoplasia



d. Ductal and glandular differentiation may occur in basal cell carcinoma. Such tumors are more common on the eyelid, face, and scalp, and display

Cysts, Pseudoneoplasms, and Neoplasms

A

215

B Fig. 6.36  Basal cell carcinoma. A, The inner aspect of the eyelids is ulcerated by the infiltrating tumor. B, Histologic section shows the morphea-like or fibrosing type, where the basal cells grow in thin strands or cords, often only one cell layer thick, closely resembling metastatic scirrhous carcinoma of the breast (“Indian file” pattern). This uncommon type of basal cell carcinoma has a much worse prognosis than the more common types (i.e., nodular [Fig. 6.35], ulcerative, and multicentric).













the presence of ducts of varying size and glandular structures occasionally suggesting apocrine secretion. e. Cystic BCC usually presents as small and multiple cysts; however, it may appear as a larger lesion that may even be translucent. It lacks apocrine gland differentiation that would be present in a BCC having ductal or glandular differentiation. f. There is a significantly increased prevalence and density of demodicosis in patients with eyelid basal cell carcinoma compared to control individuals, and may act as a triggering factor for carcinogenesis in individuals predisposed by trauma, irritation, or chronic inflammation. g. Eyelid location is a predictive factor for extensive subclinical spread of basal cell carcinoma. 2. Superficial basal cell carcinoma shows irregular buds of basaloid cells arising from a unicentric focus or multicentric foci of the epidermal undersurface. a. The cells resemble primordial germ cells. b. Tends to occur at a younger age particularly in females. 3. Micronodular type has a plaque-like shape. a. It resembles nodular BCC; however, it is smaller and forms micronodules that are approximately the size of hair bulbs. b. Minimal palisading is seen. c. The surrounding stroma is myxoid. 4. Infiltrative a. Considered a continuum between the nodular and morpheaform types. b. Different size nodules. c. Mucinous stroma. d. Invasive behavior. 5. Morpheaform (fibrosing) type a. Thin islands and strands of tumor cells that have an aggressive behavior. b. Lines of tumor cells may only be one layer thick.





c. No peripheral palisading. d. Closely resembling metastatic scirrhous carcinoma of the breast (“Indian file” pattern). e. The stroma, rather than being juicy and loose (desmoplastic), shows considerable proliferation of connective tissue into a dense fibrous stroma, reminiscent of scleroderma or morphea. The tumor strands tend to shrink in processing, leaving surrounding retraction spaces. f. In the morpheaform variant, it is difficult clinically to determine the limits of the lesion. The tumor tends to be much more aggressive, to invade much deeper into underlying tissue, and to recur more often than the nodular or superficial type. The basal cell nevus syndrome (Gorlin’s syndrome), inherited in an autosomal-dominant fashion, consists of multiple basal cell carcinomas of the skin associated with defects in other tissues such as odontogenic cysts of the jaw, bifid rib, abnormalities of the vertebrae, and keratinizing pits on the palms and soles. Histologically, the skin tumors are indistinguishable from the noninherited form of basal cell carcinoma. The defective gene is in the tumor suppressor gene PATCHED, a gene on chromosome 9q.



G. Frozen section-controlled excision is particularly important in preventing re-recurrence in recurrent BCC. H. “Horrifying basal cell carcinoma” was first used in 1973 to describe 33 cases of BCC that met the criteria of tumor size greater than 3 cm, and exhibited behavior characterized by local destruction, recurrence, and metastasis. 1. The initial report noted that these tumors were histologically indistinguishable from ordinary basal cell carcinomas.

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2. The term, “problematic aggressive” has been used to designate these tumors and BCCs that are frequently recurrent, often after histologically confirmed excision. 3. They have been associated with more aggressive pattern such as morpheaform, multifocal, and infiltrative growth. 4. Others have concluded that horrifying tumors do not have intrinsically different growth patterns or proliferation characteristics. They cite reports of denial on the part of the patient, and delay in seeking care, or inadequate early management, particularly of infiltrative tumors as key factors contributing to horrifying BCCs. I. It has been suggested that impression cytology may be useful in the diagnosis of eyelid tumors. II. Squamous cell skin carcinoma (Fig. 6.37; see Fig. 6.27) A. Squamous cell carcinoma rarely involves the eyelid, and is seen at least 40 times less frequently than eyelid basal cell carcinoma. The most frequent sites of periocular involvement are the lower eyelid (49%), medial canthus (36%), and the upper eyelid (23%). The opposite situation exists in the conjunctiva (see Chapter 7), where squamous cell carcinoma is the most common epithelial malignancy and basal cell carcinoma is the rarest.

A









B. From the 1960s to the 1980s, the incidence of squamous cell skin carcinoma increased 2.6 times in men and 3.1 times in women, attributed to presumed voluntary exposure to sunlight (ultraviolet radiation). C. Intraepidermal squamous cell carcinoma (squamous cell carcinoma in situ) 1. When epidermal atypia becomes full-thickness, intraepidermal squamous cell carcinoma (carcinoma in situ) is present. It may arise de novo or from precancerous keratoses (e.g., actinic keratosis). 2. Clinically, the area is indurated and plaquelike. 3. Histologically, the lesion resembles the precancerous keratoses except for more advanced changes. a. Carcinoma in situ is characterized by replacement of the epidermis by an atypical proliferation of keratinocytes showing loss of polarity, nuclear hyperchromatism and pleomorphism, cellular atypia, and mitotic figures. Better differentiation may be accompanied by the presence of “squamous pearls or dyskeratotic pearls” formed by clusters of abnormal gradually keratinizing atypical squamous cells. These structures must be differentiated from “horn cysts” that are common in benign squamous lesions and consist of keratinfilled cysts that do not display the gradual keratinization commonly found in dyskeratotic pearls, or with the “squamous eddy” typical of IFK. b. The overlying stratum corneum is parakeratotic.

B

Fig. 6.37  Squamous cell carcinoma. A, The patient had an ulcerated lesion of the lateral aspect of the eyelids that increased in size over many months. B, Histologic section of the excisional biopsy shows epithelial cells with an overall pink color that infiltrate the dermis deeply. The overlying region is ulcerated. C, Increased magnification shows the invasive squamous neoplastic cells making keratin (pearls) in an abnormal location (dyskeratosis). Numerous mitotic figures are present. Note the pseudosarcomatous (dysplastic) change in the surrounding stroma.

C

Cysts, Pseudoneoplasms, and Neoplasms





D. Invasive squamous cell carcinoma 1. Carcinoma in situ may remain fairly stationary or enlarge slowly and invade the dermis (i.e., invasive squamous cell carcinoma). 2. Histologically, if the intraepidermal squamous cell carcinoma penetrates through the epidermal basement membrane and invades the dermis, the lesion is classified as invasive squamous cell carcinoma. The supporting dermal stroma then undergoes a proliferative, desmoplastic, pseudosarcomatous reaction. 3. Squamous cell skin carcinomas less than 2 mm thick (approximately 50% of total) almost never metastasize (“no-risk carcinomas”); of those between 2 and 6 mm thick (moderate differentiation and invasion not extending beyond the subcutis), approximately 4.5% metastasize (“low-risk carcinomas”); and of those over 6 mm thick, especially with infiltration of the musculature, perichondrium, or periosteum, approximately 15% metastasize (“high-risk carcinomas”). 4. The rate of regional lymph node metastasis in patients with eyelid or periocular squamous cell carcinoma may be as high as 24%. Sentinel lymph node biopsy may be helpful in the evaluation of conjunctival and eyelid malignancies. a. Preoperative lymphoscintigraphy facilitates identifying sentinel lymph nodes. b. Overexpression of cluster of differentiation 44 variant 6 is correlated with the progress and metastasis of ocular squamous cell carcinoma and is associated with proliferating cell nuclear antigen labeling index. 5. Perineural invasion is an adverse prognostic finding. Cutaneous squamous cell carcinoma may show perineural spread of the neoplasm through the orbit. The tumor may also metastasize to regional lymph nodes in about 24% of patients. 6. Squamous cell carcinoma needs to be differentiated from pseudocarcinomatous (pseudoepitheliomatous) hyperplasia, which shows minimal or absent individual cell keratinization and lacks nuclear atypia (see Fig. 6.31). 7. Increased expression of αv integrin protein in squamous cell carcinoma is associated with less differentiated and more invasive lesions. Conversely, well-differentiated squamous cells and carcinoma in situ express low levels of αv integrin protein. 8. Immunoexpression of VEGF and epidermal growth factor receptor is higher in moderate/poorly differentiated eyelid squamous cell carcinomas compared to well-differentiated tumors. These markers are associated with the acquisition of aggressive and angiogenic phenotype. 9. Methylation and associated low expression of CDH1, which encodes E-cadherin, a glycoprotein that is important in cell–cell interaction, are significantly



217

associated with advanced and aggressive phenotypes of eyelid squamous cell carcinoma. In this regard, CDH1 methylation and CDH1 expression are both prognostic factors for eyelid squamous cell carcinoma. 10. Strong p16 expression was observed in all ocular surface and periorbital squamous tumors in one study. E. Bowen’s disease (intraepidermal squamous cell carcinoma, Bowen type) 1. Bowen’s disease is a clinicopathologic entity that consists of an indolent, solitary (or multiple), erythematous, sharply demarcated, scaly patch. It grows slowly in a superficial, centrifugal manner, forming irregular, serpiginous borders. The lesions may remain relatively stationary for up to 30 years. 2. Bowen’s disease is associated with other skin tumors, both malignant and premalignant, in up to 50% of patients. The suggested association with internal malignancies has not been definitely established. Arsenic concentration in Bowen’s disease lesions is high and may even cause them.

3. Rarely, Bowen’s disease may invade the underlying dermis, and then it behaves like an invasive squamous cell carcinoma. 4. Histologically, the lesion is characterized by a loss of polarity of the epidermis so that the normal epidermal cells are replaced by atypical, sometimes vacuolated or multinucleated, haphazardly arranged cells not infrequently showing dyskeratosis and mitotic figures that are often bizarre. The basal cell layer is intact, and the underlying dermis is not invaded. Histologically, the clinicopathologic entity of Bowen’s disease and intraepidermal squamous cell carcinoma unrelated to Bowen’s disease (see earlier) cannot be distinguished. Bowen’s disease is not a histopathologic diagnosis, but rather a clinicopathologic one.



F. Adenoacanthoma, a rare tumor, may represent a pseudoglandular (tubular and alveolar formations in the tumor) form of squamous cell carcinoma, or it may be an independent neoplasm. The prognosis is somewhat more favorable than for the usual squamous cell carcinoma. Clear cell acanthoma (Degos’ acanthoma) is a benign, solitary, well-circumscribed, noninvasive neoplasm. Histologically, there is a proliferation of glycogen-rich, clear, large epidermal cells.

Tumors of the Epidermal Appendages (Adnexal Skin Structures) Benign adnexal tumors include apocrine or eccrine hydrocystoma (80%), pilomatrixoma (5%), syringoma (5%), trichilemmoma

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(5%), syringocystadenoma papilliferum (2%), trichoepithelioma (1%), and trichofolliculoma (1%). I. Tumors of, or resembling, sebaceous glands A. Congenital sebaceous gland hyperplasia (organoid nevus syndrome, nevus sebaceus of Jadassohn, congenital sebaceous gland hamartoma) 1. Congenital sebaceous gland hyperplasia consists of a single, hairless patch, usually on the face or scalp that usually reaches its full size at puberty. 2. The tumor seems to be a developmental error, resulting in a localized hyperplasia of sebaceous glands frequently associated with numerous imperfectly developed hair follicles and occasionally apocrine glands. The tumor can be considered hamartomatous. Epibulbar choristoma and conjunctival choristomas, choroidal colobomas, macro optic discs, and focal yellow discoloration in the fundus may occur in the nevus sebaceus of Jadassohn. Linear nevus sebaceus syndrome consists of nevus sebaceus of Jadassohn, seizures, and mental retardation.

A

B Fig. 6.38  Adenoma sebaceum of Pringle in tuberous sclerosis. A, Clinical appearance. B, Dermal capillary dilatation and fibrosis are typical components of the lesion (i.e., angiofibroma).

3. Histologically, a group or groups of mature sebaceous gland lobules, with or without hair follicles, and frequently with underlying apocrine glands, are present just under the epidermis, along with overlying papillomatosis. Basal cell carcinoma may develop in up to 20% of the lesions, and more rarely other tumors may develop (e.g., syringocystadenoma papilliferum and sebaceous carcinoma). Moreover, syringocystadenoma papilliferum may mimic basal cell carcinoma clinically.



B. Acquired sebaceous gland hyperplasia (senile sebaceous gland hyperplasia, senile sebaceous nevi, adenomatoid sebaceous gland hyperplasia) 1. Acquired sebaceous gland hyperplasia consists of one or more small, elevated, soft, yellowish, slightly umbilicated nodules occurring on the face (especially the forehead) in the elderly. 2. Histologically, a greatly enlarged sebaceous gland is composed of numerous lobules grouped around a central large sebaceous duct. Sebaceous gland hyperplasia may follow chronic dermatitis, especially acne rosacea and rhinophyma.



C. Adenoma sebaceum of Pringle (angiofibromas of face; Fig. 6.38) 1. The small, reddish, smooth papules seen on the nasolabial folds, on the cheeks, and on the chin in people with tuberous sclerosis (Chapter 2) have been



called adenoma sebaceum (Pringle) but are truly angiofibromas. 2. Histologically, the sebaceous glands are usually atrophic. Dilated capillaries and fibrosis are seen in the smaller lesions, whereas capillary dilatation is minimal or absent in the larger lesions, where markedly sclerotic collagen is arranged in thick concentric layers around atrophic hair follicles. D. Sebaceous adenoma 1. Although rare, it has a predilection for the eyebrow and eyelid and appears as a single, firm, yellowish nodule. The presence of a solitary sebaceous gland lesion (mainly adenoma) may be associated with a visceral malignancy, primarily of the gastrointestinal tract (Muir–Torre syndrome), which is a rare autosomal dominantly inherited subtype of Lynch syndrome II and caused by DNA mismatch repair proteins. Immunohistochemical staining of eyelid sebaceous adenomas for the mismatch repair proteins mutL homologue 1 (MLH1) and mutS homologue 2 (MSH2) is useful for evaluating for Muir–Torre syndrome. Nevertheless, neither loss of mismatch repair genes, nor microsatellite instability are commonly associated with sporadic sebaceous carcinoma of the ocular adnexa. Both benign sebaceous and transitional squamosebaceous neoplasms should be considered as possible manifestations of the syndrome. Multiple sebaceous adenomas and extraocular sebaceous carcinoma have been reported in a patient with multiple sclerosis.

Cysts, Pseudoneoplasms, and Neoplasms







2. Histologically, the irregularly shaped lobules are composed of three types of cells. a. The presence of generative or undifferentiated cells, identical in appearance to the cells present at the periphery of normal sebaceous glands, allows the diagnosis to be made. b. Mature sebaceous cells. c. Transitional cells between the preceding two types. 3. Rapid growth in a sebaceous adenoma due to hyperplasia has simulated malignancy. Malignancy was excluded secondary to lack of infiltrative border, low Ki-67 index, and low proliferative ability. E. Sebaceous gland carcinoma (Fig. 6.39; see Fig. 6.4B) 1. Sebaceous gland carcinoma (SGC) is more common in middle-aged women, has a predilection for the

eyelids, and arises mainly from the meibomian glands, but also from the glands of Zeis, and sebaceous glands. a. It is the most common eyelid malignancy after basal cell carcinoma affecting in descending order the upper lid (two to three times more often than the lower), the lower lid, the caruncle, and then the brow. It accounts for only 1%–5.5% of eyelid malignancies in Caucasians; however, it represents 39% and 37.5% of eyelid malignancies in Chinese and Japanese people, respectively. 2. Clinically, a SGC is often mistaken for a chalazion. The lesion, however, may mimic many conditions, and is called the great masquerader.



A

B

C

D

Fig. 6.39  Sebaceous gland carcinoma. A, Upper-lid lesion resembles a chalazion. Note loss of cilia in area of lesion. B, Excisional biopsy shows large tumor nodules in the dermis, most of which exhibit central necrosis. C, Increased magnification shows numerous cells resembling sebaceous cells. A number of mitotic figures are present. D, Oil red-O fat stain shows marked positivity in the cytoplasm of abnormal cells. Any recurrent or suspect chalazion should be sampled for biopsy. E, In another case, large tumor cells are scattered throughout the surface epidermis, simulating Paget’s disease (i.e., pagetoid change). The cancerous invasion of the epithelium can cause a chronic blepharoconjunctivitis (masquerade syndrome). E

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a. Any recurrent chalazion should be considered for histologic study, and any chronic, recalcitrant, atypical blepharitis or atypical unilateral papillary conjunctivitis should be considered for biopsy, especially when accompanied by loss of lashes (madarosis). b. Clinical dermoscopic examination of the lesion can demonstrate polymorphous vessels with a yellowish background to assist in the diagnosis. c. SGC can be found in association with Muir–Torre syndrome (also see above). The syndrome has been reported in a patient with bilateral eyelid cancers, including SGC, and breast cancer. Mutational inactivation of p53 may be involved in the progression of sebaceous carcinoma.

3. The mortality rate is approximately 22%. Treatment by Mohs micrographic surgery may significantly reduce the mortality. Metastatic breast cancer to the eyelid margin has masqueraded as SGC.





4. Histologically, irregular lobular masses of cells resemble sebaceous adenoma but tend to be more bizarre and to show distinct invasiveness. a. Focally, cells show abundant cytoplasm signifying sebaceous differentiation. b. Fat stains of frozen sections of fixed tissue show that many of the cells are lipid-positive. c. The malignant epithelial cells may invade the epidermis, producing an overlying change resembling Paget’s disease called pagetoid change. d. In one study, immunohistochemical staining for androgen receptor and for adipophilin was found to be helpful in distinguishing among SGC, squamous carcinoma, melanoma and basal cell carcinoma. 1) SGC is positively for both stains. 2) Conversely, squamous carcinoma and melanoma stain for neither. 3) Basal cell carcinoma very rarely shows staining. 4) Androgen receptor is more helpful for detecting pagetoid spread of SGC than is adipophilin. 5) Others have supported a role for androgen receptor (NR3C4) as a significant prognostic indicator in SGC. 6) In another report, positive adipophilin staining was found in 100% of SGCs, 100% of cutaneous squamous cell carcinomas, 95% of basal cell carcinomas, 73% of conjunctival squamous cell carcinomas, and 60% of mucoepidermoid carcinomas.

7) Nevertheless, the authors concluded that the pattern and intensity of adipophilin staining were helpful in distinguishing SGC from other neoplasms with overlapping histology. 8) Additionally, factor XIIIa (AC-1A1) has proven helpful as a sensitive and specific nuclear marker for sebaceous differentiation and in complementing adipophilin in differentiating SGC from squamous cell carcinoma and basal cell carcinoma. 9) SGC immunohistochemical staining for perforin is useful for highlighting intraepithelial tumor spread, and appears better than EMA in this regard. Intraepithelial SGC (pagetoid change) can spread to the conjunctiva and cornea. Resultant diffuse loss of lashes may simulate a blepharitis. Rarely, intraepithelial sebaceous carcinoma may be the only evidence of the lesion with no underlying invasion present. The intraepithelial invasion may involve the lids and conjunctiva together, or only the conjunctiva and cornea. 10) Factors predictive of regional lymph node metastasis include duration of symptoms >6 months and orbital tumor extension. Factors predictive of systemic metastasis are orbital tumor extension and perivascular invasion. Orbital tumor invasion also predicts death due to systemic metastasis. 11) Overexpression of X-linked inhibitor of apoptosis (XIAP) has been found in 62% of eyelid SGCs, and is associated with advanced age, large tumor size, and reduced disease-free survival. 12) Low levels of MicroRNA (miRNA)-200c and miRNA-141 facilitate sebaceous tumor progression by promoting epithelialmesenchymal transition (EMT) and are predictive of shorter disease-free survival in SGC. 13) ZEB2/SIP1 also is important in regulating EMT, and down-regulates E-cadherin expression. Cytoplasmic overexpression of ZEB2 and membranous loss of E-cadherin have been seen in 68% and 66% of cases of eyelid SGC, respectively. Moreover, overexpression of ZEB2 significantly correlates with lymph node metastasis, orbital invasion, large tumor size, and advanced tumor stages. As might be anticipated, patients overexpressing ZEB2 also have poor survival. 14) Expression of ALDH1 by SGC is a predictor of a poor outcome. 15) Activation of the Shh and Wnt signaling pathway is associated with aggressive behavior in SGC.

Cysts, Pseudoneoplasms, and Neoplasms

16) Retinoic acid signaling also appears to play a role in the pathogenesis of SGC. 17) Human papilloma virus infection does not appear to be related to the development of SGC. II. Tumors of or resembling hair follicles A. Trichoepithelioma (epithelioma adenoides cysticum, benign cystic epithelioma) Trichoepithelioma is probably a special variety of trichoblastoma, characterized by its almost universal facial location, its dermal rather than subcutaneous location, its mainly cribriform pattern, and its compartmentalized clefts between fibroepithelial units. Trichoblastoma, a benign tumor of hair germ cells (follicular germinative cells), includes the entities panfolliculoma, trichoblastoma with advanced follicular differentiation, immature trichoepithelioma, and trichoepithelioma. Trichoepithelioma comprised 1.3% of 228 benign adnexal tumors in one study.





1. The tumor may occur as a small, single, rosy yellow or glistening flesh-colored nodule (Fig. 6.40), as a few isolated nodules, or as multiple symmetric nodules with onset at puberty. It occurs predominantly on the face and is inherited as an autosomal-dominant trait (Brooke’s tumor). The nodule tends to grow to several millimeters or even to 1 cm. 2. Histologically, multiple squamous cell cysts (i.e., horn cysts, consisting of a keratinized center surrounded by basaloid cells) are the characteristic finding and represent immature hair structures. a. Basaloid cells, indistinguishable from the cells that constitute basal cell carcinoma, are present around the horn cysts and in the surrounding tissue as a lacework or as solid islands. 1) They may display peripheral palisading and a follicular stroma characterized by concentric collagen. 2) Spindled fibroblasts are arranged in parallel to the periphery of the tumor nodules. b. Occasionally the cysts have openings to the skin surface and resemble abortive hair follicles. The

A

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cysts may rupture, inducing granulomatous inflammation, or they may become calcified. The horn cyst shows complete and abrupt keratinization, thereby distinguishing it from the horn pearl of squamous cell carcinoma, which shows incomplete and gradual keratinization.

3. Can be found in Brooke–Spiegler syndrome, which is associated with germline mutations in the tumor suppressor gene CYLD. B. Trichofolliculoma 1. Trichofolliculoma is found in adults and consists of a small, solitary lesion often with a central pore. a. The vast majority are on the face or ears. b. They usually are reported in adolescents or young adults; however, congenital cases do occur.





Trichoadenoma, a rare benign cutaneous tumor, resembles trichofolliculoma, but the cells appear less mature; conversely, the cells appear more mature than the cells in trichoepithelioma.

2. Histologically, a large dermal cystic space lined by squamous epithelium and containing keratin and hair shaft fragments is surrounded by smaller, welldifferentiated, secondary hair follicles. a. The stroma was composed of spindle cells, with peripheral inflammation in most cases in one report of 90 cases. b. Immunochemistry of 10 specimens from that study demonstrated intense CK17 expression in the inner and outer root sheath. c. PHLDA1 positivity was found particularly in the immature follicles. d. BerEP4 was strongly positive, especially in the peripheral immature component, forming bulbar images. e. Outer and inner root sheaths were negative. Sebaceous glands also may be seen.









B Fig. 6.40  Trichoepithelioma. A, Clinical appearance of a lesion in the middle of the right upper lid near the margin. B, Histologic section shows the tumor diffusely present throughout the dermis. The tumor is composed of multiple squamous cell horn cysts that represent immature hair structures.

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A

CHAPTER 6  Skin and Lacrimal Drainage System

B

Fig. 6.41  Trichilemmoma. A, Histologic section shows lobular acanthosis of clear cells (shown with increased magnification in B) oriented around hair follicles. C, The clear cells are strongly periodic acid–Schiff-positive.

C



C. Trichilemmoma (Fig. 6.41) 1. It tends to be a solitary, asymptomatic lesion located on the face and mainly found in middle-aged people. The lesion has no sex predilection. 2. Characteristically, trichilemmoma often shows a central pore that contains a tuft of wool-like hair.

of central desmoplasia, outer root sheath differentiation of the tumor cells, and CD34 positivity. These features help differentiate it from basal cell carcinoma.



Patients who have multiple (not solitary) facial trichilemmomas may have Cowden’s disease (multiple hamartoma syndrome), an autosomaldominant disease characterized by multiple trichilemmomas, acral keratoses, occasional Merkel cell carcinoma, oral papillomas, goiter, hypothyroidism, ovarian cysts, uterine leiomyomas, oral and gastrointestinal polyps, and breast disease.



3. Histologically, a central cystic space represents an enlarged hair follicle. a. A lobular acanthosis of glycogen-rich cells is oriented about hair follicles. b. The edge of the lesion usually shows a palisade of columnar cells that resemble the outer root sheath of a hair follicle and rest on a well-formed basement membrane. Desmoplastic trichilemmoma may simulate a verruca, follicular keratosis, or a basal cell carcinoma. It is characterized by the presence





D. Hybrid cysts 1. Have apocrine, trichilemmal and infundibular differentiation. 2. Cystic structure lined by combination of apocrine, infundibular (epidermoid) and trichilemmal epithelium. 3. Lumen contains keratin debris, and serous material. 4. Often contiguous with a hair follicle. 5. Immunohistochemistry positive for high-molecularweight cytokeratin, and cystic structures positive for carcinoembryonic antigen. 6. Origin from the junction of keratinizing squamous and glandular epithelium of the hair follicle has been suggested. E. Trichilemmal carcinoma 1. Trichilemmal carcinoma is a rare tumor that arises from the hair sheath, mainly on the face or ears of the elderly. a. It rarely involves the eyelid. b. It is locally invasive. c. Actinic damage, long-term low-dose irradiation, and transformation from benign trichilemmoma

Cysts, Pseudoneoplasms, and Neoplasms

have been postulated as possible pathogenetic mechanisms. 2. Histologically, it is composed of follicular-oriented, lobular sheets of atypical, clear, glycogen-containing cells resembling the outer root sheath of a hair follicle. a. There are prominent nucleoli, nuclear atypia, and a high mitotic rate. b. An attempt is made to form immature pilosebaceous units. c. The mitotic rate is increased. d. Immunohistochemical staining is negative for Ber-EP4. e. Histologically, it may be confused with basal cell carcinoma or trichoepithelioma. 3. Malignant proliferating trichilemmal tumor is characterized by proliferation of outer hair sheath epithelium with multiple central areas of trichilemmal keratinization. E. Calcifying epithelioma of Malherbe (pilomatricoma; see earlier section Benign Cystic Lesions). F. Adnexal carcinoma—the term adnexal carcinoma should be restricted to those tumors that are histologically identical to basal cell carcinoma, but in which the site of origin (e.g., epidermis, hair follicle, sweat gland, sebaceous gland) cannot be determined. III. Tumors of or resembling sweat glands: apocrine sweat glands are represented in the eyelids by Moll’s glands; eccrine sweat

glands are present in the lids both at the lid margin and in the dermis over the surface of the eyelid. A. Syringoma (Fig. 6.42) 1. Syringoma is a common, benign, adenomatous tumor of the eccrine sweat structure occurring mainly in young women and consisting of small, soft papules, usually only 1 or 2 mm in size, found predominantly on the lower eyelids. a. It probably arises from intraepidermal eccrine ducts. b. In a review of 244 cases, multiple lesions were noted in 76% of cases. c. The face was a preferred location in 56.7%, with eyelid involvement in 36.3%. 2. Histologically, dermal epithelial strands of small basophilic cells are characteristic, as are cystic ducts lined by a double layer of flattened epithelial cells and containing a colloidal material. The ducts often have comma-like tails that give them the appearance of tadpoles. a. A variant of syringoma is the chondroid syringoma (mixed tumor of the skin—see later) 1) The lesions are classified into an apocrine type having tubular cystic branching lumens lined by two layers of epithelial cells, and the eccrine type having small tubular lumens lined by a single layer of epithelial cells.







e

t

t

A

cs cs

C

t

B

cs

cs

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Fig. 6.42  Syringoma. A, Clinical appearance of lesions just below and nasal to seborrheic keratosis of left lower lid (same patient as in Fig. 6.29). B, Histologic section shows that the dermis contains proliferated eccrine sweat gland structures that form epithelial strands and cystic spaces (e, surface epithelium; t, tumor “ducts” and epithelial strands). C, Increased magnification demonstrates epithelial strands and cystic spaces lined by a double-layered epithelium (cs).

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2) Each of these types may have benign, atypical, and malignant variants. There is also a myxoid, adipocytic, chondroid, and/or fibrous stroma. 3) Complete excision and regular follow-up of even cytologically benign lesions are recommended because they may recur with malignant transformation. 4) Apocrine chondroid syringoma also has been reported to involve the eyelid. 5) Another syringoma variant reported to involve the eyelid is the plaque-type syringoma. B. Syringomatous carcinoma Many names have been given to the entity of syringomatous carcinoma: syringoid eccrine carcinoma, eccrine epithelioma, basal cell epithelioma with eccrine differentiation, eccrine carcinoma with syringomatous features, sclerosing sweat duct carcinoma, many examples of microcystic adnexal carcinoma, malignant syringoma, sclerosing sweat duct syringomatous carcinoma, sweat gland carcinoma with syringomatous features, basal cell carcinoma with eccrine differentiation, and eccrine basaloma. About 80% of cases of microcystic adnexal carcinoma that have histopathology checked are misdiagnosed initially.







1. The tumor usually occurs as a single nodule and can be classified as well, moderately, or poorly differentiated syringomatous carcinoma. a. Well-differentiated syringomatous carcinoma is characterized by many discrete tubules, lack of nuclear atypia, some mitotic figures, often aggregations of cells showing a solid basaloid or cribriform, adenoid cyst-like pattern, and usually desmoplastic or sclerotic stroma. b. Moderately differentiated syringomatous carcinoma consists of easily recognized, well-formed tubules, nuclear atypia, few or no mitotic figures, and usually desmoplastic or sclerotic stroma.

A



c. Poorly differentiated syringomatous carcinoma consists of focal subtle tubular differentiation, striking nuclear atypia, numerous mitotic figures, strands of neoplastic cells between collagen bundles, and usually desmoplastic or sclerotic stroma. 2. Infiltration of the underlying subcutaneous tissue, perineural spaces, and muscle, often with focal inflammation, is common. 3. In addition to PAS positivity in some lumina and lining cells, immunohistochemical staining is positive for S-100 protein, high-molecular-weight cytokeratins (AE1/AE3), and epithelial membrane antigen (negative for K-10 and the low-molecular-weight cytokeratin CAM 5.2). C. Syringocystadenoma papilliferum (papillary syringadenoma) (Fig. 6.43) 1. Syringocystadenoma papilliferum is usually classified an adenoma of apocrine sweat structures that differentiates toward apocrine ducts, although some have claimed an eccrine origin for the lesion. 2. The lesion is usually solitary and occurs in the scalp as a hairless, smooth plaque until puberty, after which it becomes raised, nodular, and verrucous. In one study of 14 patients, 64% of the lesions were associated with other apocrine, eccrine, or sebaceous tumors or malformations; none of which were malignant. In 75% of cases, the lesion arises in a pre-existent nevus sebaceus (see elsewhere in this chapter); the other 25% occur as an isolated finding. Malignant tumors, particularly basal cell carcinoma, may arise in association with syringocystadenoma papilliferum developing with nevus sebaceus.



3. Histologically, the epidermis is papillomatous. a. One or more cystic invaginations (frequently forming villus-like projections), lined by a double layer of cells composed of luminal high columnar

B

Fig. 6.43  Syringocystadenoma papilliferum of the eyelid. A, Lower power demonstrates papillary configuration. B, Higher magnification demonstrates papillary structure is lined by bilayered apocrine epithelium. (Courtesy of Dr. Tatyana Millman.)

Cysts, Pseudoneoplasms, and Neoplasms







cell hidradenoma shows two cell types: a polyhedral to fusiform cell with slightly basophilic or eosinophilic cytoplasm, and a clear (glycogen-containing) cell. The epithelial cells stain positively for cytokeratins AE1 and AE3 (high-molecular-weight cytokeratins), epithelial membrane and carcinoembryonic antigens, and muscle-specific actin. Although the clear cell hidradenoma is thought to be of eccrine origin, it may be of apocrine gland origin. A further variant of the clear cell hydradenoma is the apocrine mixed tumor. The histologic appearance is the same as that of the lacrimal gland mixed tumor. A more probable variant of eccrine spiradenoma is the eccrine hidrocystoma (see earlier subsection Benign Cystic Lesions). Hidradenoma papilliferum usually is found in the anogenital, periumbilical, and axillary areas as an adenoma with apocrine differentiation. As an ectopic lesion, it may appear on the head and neck, but only very rarely on the eyelid where it may be solid or cystic. Histochemical features include periodic acid–Schiff positive, diastase resistant granules in luminal cells. These cells also are positive for nonspecific esterase and acid phosphatase. The differential diagnosis includes: syringocystadenoma, which would be suggested by the presence of a plasma cell infiltrate; tubular apocrine adenoma, which would be suggested by the presence of a lobular pattern, and tubular apocrine structures with an epidermal connection; and clear-cell adenoma, which is suggested by cytoplasmic clearing.

cells and outer myoepithelial cells, extend into the dermis. b. The cystic spaces open from the surface epithelium rather than representing closed spaces entirely within the dermis. 4. Squamous carcinoma has developed in syringocystadenoma papilliferum of the eyelid. a. In a report of 10 cases of carcinoma, one was found to arise in a previously existing syringocystadenoma papilliferum. b. Apocrine differentiation with decapitation was present in 4 cases. c. Regional lymph node metastasis occurred in 4 patients. d. Histologically, papillations were lined by two layers of epithelium, an outer basal layer of small cuboidal cells and an inner luminal layer of columnar cells. 1) The inner layer of cells displayed loss of polarity. 2) The neoplastic cells displayed significant nuclear and cellular atypia with some cells exhibiting large nuclei and prominent nucleoli. 3) Abnormal mitotic figures were seen. 4) Invasion was seen in 9 cases. In most cases, a heavy plasma cell inflammatory infiltrate is present. Congenital abnormalities of sebaceous glands and hair follicles are often also present.







D. Eccrine spiradenoma (nodular hidradenoma, clear cell hidradenoma, clear cell carcinoma, clear cell myoepithelioma, myoepithelioma) 1. Eccrine spiradenomas usually occur in adults as deep, solitary, characteristically painful dermal nodules that arise from eccrine structures. 2. Histologically, the tumor is composed of one or more basophilic dermal islands arranged in intertwining bands, as well as tubules containing two types of cells and surrounded by a connective tissue capsule. a. Small, dark cells with dark nuclei and scant cytoplasm are present toward the periphery of the bands and tubules. b. Cells with large, pale nuclei and scant cytoplasm are present in the center of the bands and tubules, and line the few small lumina usually present. A possible variant of the eccrine spiradenoma is a tumor composed primarily of cells containing clear cytoplasm called a clear cell hidradenoma (eccrine acrospiroma, clear cell myoepithelioma, solid cystic hidradenoma, clear cell papillary carcinoma, porosyringoma, nodular hidradenoma). An intradermal nodule that may ulcerate or enlarge rapidly secondary to internal hemorrhage, the clear

225



E. Eccrine mixed tumor (chondroid syringoma; see earlier) 1. Eccrine mixed tumor is rarer than the apocrine mixed tumor, but is histologically similar. 2. Histologically, it has tubular lumina lined by a single layer of flat epithelial cells. Conversely, the epithelial lining of apocrine mixed tumors is larger, more irregularly shaped, and consists of at least a double layer of epithelial cells.







a. The epithelial lining stains positively for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen. b. The outer cell layers stain positive for vimentin, S-100 protein, neuron-specific enolase, and sometimes glial acidic protein. The stroma stains immunohistochemically like the outer cell layers. F. Cylindroma (turban tumor) 1. Cylindroma is probably of apocrine origin, is benign, often has an autosomal-dominant inheritance pattern, has a predilection for the scalp, and appears in early adulthood.

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CHAPTER 6  Skin and Lacrimal Drainage System

a. Cylindromas and trichoepitheliomas are frequently associated and may occur in such numbers as to cover the whole scalp like a turban, hence the name turban tumor as seen in Brooke–Spiegler syndrome. 1) This syndrome is autosomal dominant in inheritance. 2) It is associated with adenoma and carcinoma of the parotids, sebaceous nevus, basocellular carcinomas, milium, xeroderma pigmentosa, hypo- and hyperchromia, polycystosis of the lungs, kidneys, breast, and multiple fibromas. 3) Malignant transformation of the associated cylindromas may occur with possible metastasis. 4) The tumors also may infiltrate the skull. 5) The development of multiple adnexal tumors such as cylindromas, trichoepitheliomas, and spiradenomas may occur. 6) This syndrome is caused by a mutation in the CYLD gene on chromosome 16. 2. Histologically, islands of cells fit together like pieces of a jigsaw puzzle and consist of two types of cells, irregular in size and shape, separated from each other by an amorphous, hyaline-like stroma: cells with small, dark nuclei and scant cytoplasm are found in the periphery of the islands; and cells with large, pale nuclei and scant cytoplasm are present in the center of the islands. Tubular lumina are usually present and are lined by cells demonstrating decapitation secretion, like cells seen in apocrine glands. G. Eccrine poroma 1. Eccrine poroma is a common, benign, slowly growing tumor that seldom involves the eyelid. 2. It usually occurs on the soles of the feet as firm, dome-shaped, slightly pedunculated, pinkish-red tumors, but it may occur elsewhere. 3. It arises from the eccrine duct as it courses through the epidermis. 4. Histologically, it consists of intraepidermal masses of cells connected by cellular bridges and resemble squamous cells, but are more cuboidal and smaller, and have a basophilic nucleus that thicken the epidermis and extend down into the dermal area. Small ductal lumina are usually present and are lined by a PAS-positive, diastase-resistant cuticle.

Eccrine porocarcinoma is a rare form of eccrine adenocarcinoma. Most commonly it arises on the lower extremity and has a variable prognosis. Rarely it has been reported to occur on the eyelid.



H. Oncocytoma 1. Oncocytoma may occur in the caruncle (see Fig. 7.22), lacrimal gland, lacrimal sac, and much more rarely on the lids. It arises from apocrine glands.



2. Histologically, the tumor usually shows cystic and papillary components. Electron microscopy shows malformed mitochondria in the tumor cells. I. Sweat gland carcinomas are rare. 1. Eccrine sweat gland carcinomas Two groups occur: one arises from benign eccrine tumors (or de novo) as a malignant counterpart. These include eccrine porocarcinoma, malignant eccrine spiradenoma, malignant hidradenoma, and malignant chondroid syringoma. The second group comprises primary eccrine carcinomas and includes classic eccrine adenocarcinoma (ductal eccrine carcinoma), syringomatous carcinoma (see earlier), microcystic adnexal carcinoma (see later), mucinous (adenocystic) carcinoma, and aggressive digital papillary adenocarcinoma. Mucinous eccrine adenocarcinoma is a rare ocular adnexal tumor that can involve the eyelid and periocular skin, can be locally invasive, and has a high risk of local recurrence even after Mohs surgery. Nevertheless, the prognosis following excision with confirmed tumor-free margins is good.







a. They have a tubular, or rarely, an adenomatous (adenocarcinoma) structure, or even more rarely a histiocytoid variant. b. Histologically, it is difficult to differentiate eccrine carcinoma from metastatic carcinoma; the diagnosis of metastatic carcinoma, therefore, should always be considered before making a final diagnosis of eccrine carcinoma. c. Microcystic adnexal carcinoma 1) Usually solitary and occurs as a nodule or indurated, deep-seated plaque. Many tumors previously diagnosed as microcystic adnexal carcinomas are really syringomatous carcinoma. Also, signet-ring cell carcinoma of the eccrine sweat glands of the eyelid should not be confused with syringomatous carcinoma.

2) In the superficial part of the tumor, small keratocytes are often seen, whereas deeper in the tumor, microtubules and thin trabeculae predominate. 3) Infiltration of the underlying subcutaneous tissue, perineural spaces, and muscle, often with focal inflammation, is common. 4) The histogenesis is unknown—theories include eccrine and pilar origin. 2. Apocrine sweat gland carcinomas (from Moll’s glands in the eyelid) are adenocarcinomas and occur in two varieties: a ductopapillary tumor located exclusively in the dermis, and an intraepidermal proliferation (i.e., extramammary Paget’s disease) that rarely invades the dermis. Apocrine carcinoma of the eyelids

Cysts, Pseudoneoplasms, and Neoplasms

may demonstrate an aggressive behavior, including distant metastasis. a. Primary signet-ring/histiocytoid tumors of the eyelid are extremely rare, but most commonly present on the eyelid and can resemble chronic inflammation or a chalazion. b. They are slow growing and locally aggressive, but the tumor can metastasize. 1) Infiltration to involve the upper and lower eyelids may produce a monocle-like appearance, which has resulted in the appellation, “monocle tumor.” c. Most commonly affect elderly men. d. Histopathology characterized by infiltration of the dermis by single cells, or cords of single rows of cells between collagen bundles. 1) In eyelid lesions, the epidermis is not involved. 2) Cells have a bland character with histiocytoid morphology.







227

3) Cytoplasmic inclusions producing the signetring appearance are PAS and colloidal iron positive. e. Both apocrine and eccrine origins have been proposed, but more recent reports suggest an apocrine origin, possible from glands of Moll based on MUC6 and GCDFP15 immunopositivity. 1) GCDFP15, ER and PgR expression are useful in distinguishing the primary eyelid tumor from those with a gastrointestinal origin. 2) Must be differentiated from metastasizing histiocytoid mammary carcinoma. f. Excision with wide margins has been recommended for this lesion. 3. Primary mucinous carcinoma (adenocystic, colloid, mucinous eccrine carcinoma) (Fig. 6.44) a. Rare, low-grade, carcinoma. b. It is believed to arise from the deepest portion of the eccrine sweat duct.







A

B

C

D Fig. 6.44  Primary mucinous carcinoma. A, Clinical photograph of upper eyelid lesion. B, Cystic lesion with pools of mucin. C, Higher magnification shows islands of neoplastic cells floating in mucin pools with intervening fibrous septa. The tumor cells have a solid to cribriform arrangement. D, Island of basaloid tumor cells with a round to cuboidal shape, moderate amount of cytoplasm, and relatively few mitoses. (From Papalas JA, Proia AD: Primary mucinous carcinoma of the eyelid: A clinicopathologic and immunohistochemical study of 4 cases and an update on recurrence rates. Arch Ophthalmol 128:1160, 2010.)

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c. 38% occur on the eyelid. d. Histopathology demonstrates an unencapsulated, dermis-based tumor containing islands of basaloid cells with solid to cribriform pattern. 1) The tumor cells are found in basophilic, PASpositive, Alcian blue-positive, mucicarminepositive, and hyaluronidase-resistant mucin pools, which may have fibrous septae. 2) The tumor cells are round to cuboidal with moderate cytoplasm and a low mitotic rate. 3) May be positive for cytokeratins (CK7, CAM5.2), carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), estrogen receptor (ER), progesterone receptor (PR), p63, mucous-associated peptides of the trefoil factor family (TFF1 and 3), and tumor-associated glycoprotein (TAG-72). 4) It must be differentiated from metastatic tumors. e. Recurrence rate may be reduced utilizing Mohs surgery or excision with frozen section control. f. Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade sweat gland carcinoma with a predilection for the eyelid. 1) Presents as a slowly growing cyst or swelling. 2) Tend to be well-circumscribed and multinodular. 3) Have papillary areas and may have focal cribriform arrangement. 4) Composed of small- to medium-sized oval to polygonal cells with lightly eosinophilic to bluish cytoplasm. 5) Bland nuclei and mitotic activity present, but not brisk. 6) Intracytoplasmic and extracellular mucin is present. 7) Characteristically display neuroendocrine markers. 8) Associated with cystic areas lined by benign epithelium resembling that from eccrine ducts. 9) Myoepithelial cells may be present in areas of in situ carcinoma. 10) Postulated to represent a progression from noninvasive sweat gland neuroendocrine carcinoma to endocrine mucin-producing carcinoma. 11) Wilms tumor 1 (WT1) protein is expressed in the neoplastic cells of EMPSGC, areas of atypical intraductal proliferations, and mucinous carcinoma; however, there is absence of WT1 expression in areas of benign eccrine cyst and cutaneous sweat glands. These findings have suggested to some that upregulation of WT1 plays a role in tumor cell proliferation and progression of EMPSGC to primary cutaneous mucinous carcinoma.

Merkel Cell Carcinoma (Neuroendocrine Carcinoma, Trabecular Carcinoma) (Fig. 6.45) I. The Merkel cell, first described by Friedrich Merkel in 1875, is a distinctive, nondendritic, nonkeratinocytic epithelial clear cell believed to migrate from the neural crest to the epidermis and dermis.

Merkel cells, specialized epithelial cells that probably act as touch receptors, are sporadically present at the undersurface of the epidermis. Other specialized cells present in the epidermis include the three types of dendritic cell (i.e., Langerhans’ cells, melanocytes, and the intermediate dendritic cells).



A. Tumors arising from Merkel cells occur on the head and neck area, the trunk, arms, and legs, mainly (75%) in patients 65 years of age or older. Merkel cell carcinoma, like other neuroectodermal tumors (e.g., neuroblastoma, malignant melanoma, and pheochromocytoma), may show a distal deletion involving chromosome 1p35–36. Also, Merkel cell carcinoma may occur in Cowden’s disease (see earlier discussion of trichilemmoma).



B. Clinically, the most common appearance is that of a nonulcerated, violaceous nodule. C. The tumor is aggressive, has variable clinical manifestations, tends to spread early to regional lymph nodes, and should probably be treated with radical surgical therapy. There is a high rate of local recurrence (14%), regional lymph node invasion (20%), and metastasis (5%). D. Increasing in incidence at a rate of 8% annually. II. Histologically, they resemble a primary cutaneous lymphoma or cutaneous metastasis of lymphoma or carcinoma. A. The tumor is composed of solid arrangements of neoplastic cells, simulating large-cell malignant lymphoma cells, separated from the epidermis by a clear space. There is a high mitotic rate. B. Immunohistochemical staining is strongly positive for neuron-specific enolase, chromogranin, and cytokeratins 8, 18, and 19 (low-molecular-weight type); it is weakly positive for synaptophysin, but negative for leukocytic markers. C. Electron microscopy shows characteristic membranebound, dense-core neurosecretory granules; paranuclear aggregates of intermediate filaments; and cytoplasmic actin filaments. III. DNA for Merkel polyomavirus is present in 80% of the tumors, and may play a role in its pathogenesis. IV. There is an increased incidence in older immunosuppressed patients.

Normal Anatomy

A

B

C

D

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Fig. 6.45  Merkel cell tumor. A, Patient has lesions on the middle portion of upper lid. B, Excisional biopsy shows nests of dark, poorly differentiated cells in the dermis. C, Increased magnification demonstrates round cells that resemble large lymphoma cells. Numerous mitotic figures are seen. D, Electron micrograph shows the nucleus in the upper right corner. Many cytoplasmic, small, dense-core, neurosecretory granules are seen. (Case presented by Dr. DA Morris at the meeting of the Eastern Ophthalmic Pathology Section, 1985; D, courtesy of Dr. A di Sant’Agnese and Ms. KWJ de Mesy Jensen.)

Malacoplakia

Metastatic Tumors

I. Malacoplakia is a rare disorder in which tumors occur subjacent to an epithelial surface. A. Malacoplakia often arises in immunodeficient or immunosuppressed patients. B. It is characterized by persistent bacterial infection. In 90% of cases it is a coliform organism most often Escherichia coli. C. It probably is related to deficient cytoplasmic levels of cyclic guanine monophosphate in histiocytes within the lesion. II. Histologically, aggregates of histiocytes (von Hansemann histiocytes) contain characteristic inclusions (Michaelis– Gutmann bodies, which represent partially degraded organisms).

I. Metastasis to the eyelids is uncommon and usually a late manifestation of the disease. A. The most frequent primary tumor is breast carcinoma, followed by lung carcinoma and cutaneous melanoma. B. Rarer primary tumors include stomach, colon, thyroid, parotid, and trachea carcinomas. C. Although metastatic cancer is usually unilateral, the presence of lesions involving eyelids of both eyes does not exclude the possibility of metastatic disease. II. The histologic appearance depends on the nature of the primary tumor.

Pigmented Tumors See Chapter 17.

Mesenchymal Tumors The same mesenchymal tumors that may occur in the orbit may also occur in the eyelid and are histopathologically identical (see subsection Mesenchymal Tumors in Chapter 14).

LACRIMAL DRAINAGE SYSTEM NORMAL ANATOMY (Fig. 6.46) The excretory portion of the lacrimal system consists of the canaliculi (upper and lower), common canaliculus, lacrimal sac, and nasolacrimal duct. The nasolacrimal apparatus develops during the sixth week of prenatal life as a line of epithelium formed by the overlapping of lateral nasal processes by the

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3–5 mm

2 mm

8 mm

10 mm

12 mm 5 mm Fig. 6.46  Schematic functional anatomy of the lacrimal excretory system. (From de Toledo AR, Chandler JW, Buffman FV: Lacrimal system: Dry-eye states and other conditions. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 8. © Elsevier 1994.)

maxillary processes. The height of the bony nasolacrimal duct increases 1.8-fold, the average diameter increases 1.4-fold, and the volume increases 4.6-fold between two weeks and 34 months of age. Most of the increase occurs during the first 6 months of life. I. Tears pool toward the medial canthus at the lacus lacrimalis and then enter the lacrimal puncta that lie near the nasal end of each eyelid. A. The lower punctum lies slightly lateral to the upper. B. Normally, both are turned inward to receive tears, and therefore are not visible to direct inspection. C. The puncta vary from 0.5 to 1.5 mm in diameter. II. The canaliculi are lined by stratified, nonkeratinized squamous epithelium. III. The lacrimal sac is also lined with nonkeratinized squamous epithelium but, unlike the canaliculi, it contains many goblet cells and foci of columnar ciliated (respiratory-type) epithelium. The vascular plexus (cavernous body) that surrounds the lacrimal sac and nasolacrimal duct is subject to autonomic control and plays an important role in regulating the rate of tear outflow. IV. The nasolacrimal duct occupies roughly 75% of the 3- to 4-mm-wide bony nasolacrimal canal. Many so-called valves have been described in the duct, but these represent folds of the mucosa rather than true valves, although presumably they may retard flow in some individuals. V. Tear duct-associated lymphoid tissue is commonly found in individuals with symptomatically normal nasolacrimal ducts, and appears to be most associated with the scarring of symptomatic dacryostenosis.

CONGENITAL ABNORMALITIES Atresia of the Nasolacrimal Duct I. The nasolacrimal duct usually becomes completely canalized and opens into the nose by the eighth month of fetal life. II. The duct may fail to canalize (usually at its lower end) or epithelial debris may clog it.

III. Most ducts not open at birth open spontaneously during the first 6 months postpartum. IV. Congenital dacryocystocele is a rare anomaly accompanied by swelling of the lacrimal sac that is present at birth and resulting from obstruction of the lacrimal system either above or below the lacrimal sac.

Atresia of the Punctum I. Atresia of the punctum may occur alone or be associated with atresia of the nasolacrimal duct. II. An acquired form may result secondary to scarring from any cause. Lacrimal outflow dysgenesis may involve multiple components of the system, including absent or hypoplastic punctum, canaliculus, lacrimal sac, and/or nasolacrimal duct. The dysgenesis is proximal in 89%, distal in 33%, and both in 22%. Systemic syndrome or dysmorphism is present in 40% of cases and positive family history is noted in 36%.

III. Punctal stenosis may be an acquired condition having a variety of causes, including chronic blepharitis (45%), unknown etiology (27%), ectropion (23%), and drug-related (5%). Punctal stenosis may be accompanied by obstruction of the lacrimal drainage system at other levels.

Congenital Fistula of Lacrimal Sac (Minimal Facial Fissure) I. An opening of the lacrimal sac directly into the nose (internal fistula) or out on to the cheek (external fistula—the more common of the two) is a not uncommon finding. II. The opening, which may be unilateral or bilateral, is quite narrow and may be overlooked. There are many other anomalies of the lacrimal puncta, canaliculus, sac, and nasolacrimal duct, but these are beyond the scope of this book.

INFLAMMATION—DACRYOCYSTITIS (Fig. 6.47) Blockage of Tear Flow Into the Nose I. Most inflammations and infections of the lacrimal sac are secondary to a blockage of tear flow at the level of the sac opening into the nasolacrimal duct or distal to that point. II. A cast of the lacrimal sac (see Fig. 4.12) may be formed by Streptothrix (Actinomyces), which also can cause a secondary conjunctivitis. III. Treatment for dry-eye syndromes utilizing punctal plugs or of canalicular injury with stents may occasionally result in pyogenic granuloma formation. Such lesions may eventuate in extrusion of the punctal plug in 4.2% of such plugs. Other complications have been reported. IV. Lacrimal sac biopsies represent approximately 1.8% of the specimens sent to a busy ophthalmic pathology laboratory.

Inflammation—Dacryocystitis

A

231

B

Fig. 6.47  Dacryocystitis. A and B, The patient had a history of tearing and a lump in the region of the lacrimal sac. Pressure over the lacrimal sac shows increasing amounts of pus coming through the punctum. C, Another patient had an acute canaliculitis. A smear of the lacrimal cast obtained at biopsy shows large colonies of delicate, branching, intertwined filaments characteristics of Streptothrix (Actinomyces).

C

The most common diagnoses are: nongranulomatous inflammation (85.1%), granulomatous inflammation consistent with sarcoidosis (2.1%), lymphoma (1.9%), papilloma (1.11%), lymphoplasmacytic infiltrate (1.1%), transitional cell carcinoma (0.5%), and single cases of adenocarcinoma, undifferentiated carcinoma, granular cell tumor, plasmacytoma, and leukemic infiltrate. Another study of the histopathology of the lacrimal drainage system found the following diagnoses: dacryocystitis (79%), dacryolithiasis (7.9%), tumor (4.5%), trauma (3.0%), congenital malformation (1.4%), canaliculitis (1.2%), and granulomatous inflammation (1.2%). B-cell lymphoma was the most common malignant tumor detected. There is some disagreement regarding the relative involvement of the lacrimal drainage system by leukemia/lymphoma, and leukemia may be the more common lesion. Nevertheless, even NK/T-cell lymphoma has occurred in the lacrimal sac.



A. Unsuspected malignant tumor is found in lacrimal sac biopsy in 0.6% to 2.1% of cases with a clinical diagnosis of dacryocystitis/lithiasis. Routine submission of lacrimal sac biopsy tissue taken during dacryocystorhinostomy surgery for histopathological examination has been recommended. 1. Granulomatosis with polyangiitis (Wegener’s granulomatosis) may rarely involve the wall of the lacrimal sac and present as a mass lesion.

2. Canaliculitis and dacryolith formation are uncommon in children but may occur as a cause of chronic or recurrent nasolacrimal obstruction in them. a. Plasmacytoma of the canaliculus has presented as canaliculitis. 3. Hematoma of the lacrimal sac may mimic a tumor. 4. Adenocarcinoma of the lacrimal sac may arise from pleomorphic adenoma. Another rare tumor that has arisen in this region is mucoepidermoid carcinoma. V. Treatment with docetaxel may result in lacrimal drainage obstruction by inducing stromal fibrosis in the mucosal lining of the lacrimal drainage apparatus. VI. Rarely, nasolacrimal duct obstruction may result from ethmoiditis producing symptoms suggestive of acute dacryocystitis. VII. Ascending inflammation from the nose or descending inflammation from the eye may precipitate and maintain a cascade of changes that contribute to acquired malfunction of the lacrimal drainage system. VIII. Several terms are used to designate specific types of lacrimal sac cystic dilation. A. Dacryocystocele: generic term referring to any cystic dilation of the lacrimal sac resulting from proximal and distal obstruction to the drainage system. They most commonly are found in newborn infants. B. Dacryocystomucocele: contains mucus.

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C. Dacryocystomucopyocele: implies purulent material admixed with mucus and the presence of infection (dacryocystitis). 1. Giant dacryocystomucopyocele resulting in globe displacement and enlargement of the nasolacrimal duct has been reported.

majority are epithelial in origin (73%), and of these, 75% are malignant. C. Histology 1. The papillomas may be squamous (see Chapter 7), transitional, or adenomatous.



Rarely, a lacrimal sac papilloma may undergo oncocytic metaplasia (i.e., an eosinophilic cystadenoma or oncocytoma).

TUMORS Epithelial Malignant tumors constitute 70% of lacrimal sac neoplasms and squamous cell carcinoma accounts for most of these lesions. I. From lacrimal sac lining epithelium A. The epithelial lining of the lacrimal sac is the same as the rest of the upper respiratory tract (i.e., pseudostratified columnar epithelium).

2. Squamous cell carcinomas (Fig. 6.48) are identical to those found elsewhere (see Chapter 7) and are the most common. 3. Transitional cell carcinomas are composed of transitional cell epithelium showing greater or lesser degrees of differentiation. 4. Inverted papilloma is an uncommon neoplasm that has a tendency to recur, is associated with malignancy, and may invade adjacent structures. It has been reported to invade the orbit through the nasolacrimal duct. 5. Primary lymphoma of the lacrimal drainage system is extremely rare, and is usually a B-cell lesion when it does occur. Female sex may be an unfavorable prognostic factor for these lesions. Primary nonHodgkin’s lymphoma has rarely been reported to involve the lacrimal sac in children.

Tumors, therefore, are similar to those found elsewhere in the upper respiratory system, namely, papillomas, squamous cell carcinomas, transitional cell carcinomas, and adenocarcinomas.



HPV appear to be involved in the genesis of both benign (HPV 11) and malignant (HPV 18) neoplasms of the epithelium of the lacrimal sac. B. Tumors of the lacrimal sac, however, are relatively rare. They usually cause early symptoms of epiphora. The

A

B

Fig. 6.48  Squamous cell carcinoma of the lacrimal sac. A, Clinical appearance of tumor in region of right lacrimal sac. B, Strands and cords of cells are infiltrating the tissues surrounding the lacrimal sac. C, Increased magnification shows the cells to be undifferentiated malignant squamous cells. (Case presented by Dr. AC Spalding to the meeting of the Verhoeff Society, 1982.)

C

Tumors

6. Cytokeratin-negative undifferentiated (lymphoepithelial) carcinoma has been reported to involve the lacrimal sac. a. The lesion is associated with Epstein–Barr virus infection. b. Usually the tumor expresses cytokeratin. c. 5-year survival rate is from 58% to 75%. II. From lacrimal sac glandular elements A. Benign 1. Oncocytoma (eosinophilic cystadenoma) 2. Benign mixed tumor (pleomorphic adenoma) 3. Adenoacanthoma B. Malignant 1. Oncocytic adenocarcinoma 2. Adenoid cystic carcinoma 3. Adenocarcinoma

Melanotic Melanotic tumors arising from the lacrimal sac (i.e., malignant melanomas) are quite rare and are similar histologically to those found in the lid (see section Melanotic Tumors of Eyelids in Chapter 17).

Mesenchymal The same mesenchymal tumors that may involve the lids and orbit may involve the lacrimal sac (see subsection Mesenchymal Tumors in Chapter 14).

233

Miscellaneous I. Localized amyloidosis may rarely involve the lacrimal sac and nasolacrimal duct, resulting in tearing. II. Concretions actually are not calcified so terms “dacryolith and “mucolith” not appropriate. A. Mucopeptide 1. Found only in the lacrimal sac. 2. Lack cellular components. 3. Composed of amorphous, eosinophilic material that is acellular. 4. Stains positively with periodic acid–Schiff stain. B. Bacterial 1. Found mostly in the canaliculus. 2. Consist of matted filamentous organisms consistent with Actinomyces. a. May be associated with cocci organisms. C. Mixed 1. Combination of the previous two types. 2. Infrequently encountered.   References available online at expertconsult.com.

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CHAPTER 6  Skin and Lacrimal Drainage System

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