Ocular Melanocytic Tumors

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17

Ocular Melanocytic Tumors

Normal Anatomy

Ocular Melanocytes

I. Conjunctival and uveal melanocytes (Fig. 17.1) are derived from the neural crest; pigment epithelial (PE) cells are derived from neuroepithelium or the layers of the optic cup.

image
Fig. 17.1 Ocular melanocytes. Normally, the epidermal melanocytes appear in hematoxylin and eosin-stained sections as clear cells wedged between basal epithelial cells. Melanin is transferred by the dendritic processes of the melanocytes to the basal keratocytes, where it is stored and later degraded. A, In this tangential section of “reactive” epidermis, the usually clear melanocytes contain pigment around their nuclei and in their dendritic processes, making them easily visible (see Fig. 1.27C). B, A flat preparation of retinal pigment epithelium (RPE) of owl monkey shows the epithelial sheet configuration. RPE cells have a basement membrane (inner or cuticular portion of Bruch’s membrane) and are attached to one another near their apexes by terminal bars that contain “tight junctions.” C, Cross-section of the retina and choroid compares the epithelial nature of RPE with the nonepithelial individual and solitary choroidal melanocytes. The RPE cells have larger pigment granules than the choroidal melanocytes (see Fig. 9.2C). D, Thin section shows RPE pigment granules are considerably larger than those in choroidal melanocytes. Large nonpigmented cells in choroid (center toward bottom) are probably ganglion cells.

II. Dermal and conjunctival melanocytes are solitary dendritic cells.

III. Uveal melanocytes are also solitary and dendritic, and their cytoplasm contains fine, dustlike, ovoid melanin granules of a size bordering on the limits of resolution of the light microscope.

Cultured human melanocytes from different-colored eyes can produce melanin in vivo. The color of the iris is determined by the density of melanocytes in the most anterior portion of the iris (the anterior border layer).

IV. Pigment epithelium is neither solitary nor dendritic, but it is epithelial and exists as a sheet of cuboidal cells containing large, easily visualized pigment granules.

The cytoplasm of PE cells contains two basic types of pigment granules: melanin granules, which are either ovoid or spherical, and lipofuscin granules, which are usually somewhat spherical.

V. Dermal, conjunctival, and uveal melanocytes tend to vary in size, number, and melanin content among the races.

VI. Normal PE tends to vary little, if at all, among the races, and always appears heavily pigmented.

VII. Dermal, conjunctival, and uveal melanocytes almost never undergo reactive (nonneoplastic) proliferation in normal circumstances. Neoplastic proliferation, however, does occur.

VIII. The PE readily undergoes reactive proliferation but rarely becomes neoplastic.

IX. Dysplastic nevus syndrome is associated with an increased prevalence of conjunctival nevi, iris nevi, iris freckles, and choroidal nevi. It has been postulated that such individuals may have overstimulation of the melanocytic system not only in the skin but also in ocular tissues, possibly increasing the risk for melanocytic malignancies.

Dysplastic nevus may be associated with neurofibromatosis type 1.

X. Melanocytic lesions of the conjunctiva suspicious enough to require biopsy are uncommon. Among 10,675 lesions examined in the ophthalmic pathology laboratory of McGill University, there were a total of 271 (2.5%) conjunctival lesions, of which 101 were melanocytic, 44 nevi, 33 primary acquired melanosis, and eight melanomas (after excluding referred lesions).

XI. Sentinel lymph node biopsy is helpful in identifying micrometastasis for lesions involving the ocular adnexa (eyelid or conjunctiva) and can be helpful in prognosis.

Melanotic Tumors of Eyelids

Ephelis (Freckle)

Lentigo

I. Lentigo

A. Lentigo is similar clinically to an ephelis but is somewhat larger.

B. In addition to hyperpigmentation of the basal cell layer of epithelium, increased numbers of melanocytes are present. It also may be found on nonexposed skin in older people.

C. Multiple lentigines syndrome

1. Multiple lentigines syndrome also goes by the acronym LEOPARD (lentigines, multiple; electrocardiographic conduction defects; ocular hypertelorism; pulmonary stenosis; abnormal genitalia; retardation of growth; and deafness, sensorineural).

2. In addition to ocular hypertelorism (occurring in 40% of patients), other ocular findings include ptosis, microcornea, cortical punctate lenticular opacities and anterior subcapsular and zonular cataracts, patches of myelinated nerve fibers, flat pigmented spots of the iris, and glaucoma.

Multiple lentigines also occur in Carney’s syndrome (complex; see Chapter 7). Carney’s syndrome has an autosomal-dominant inheritance pattern and consists of bilateral, primary, pigmented, nodular adrenocortical hyperplasia; multiple lentigines, especially of the head and neck, and blue nevi; cutaneous myxomata; large cell, calcifying Sertoli’s cell tumor of testes; cardiac myxoma; myxoid fibroadenomas of breast; pituitary tumors (which may lead to Cushing’s syndrome); and melanotic schwannomas.

D. Lentigo maligna (melanotic freckle of Hutchinson; circumscribed precancerous melanosis of Dubreuilh; Fig. 17.2)

1. Lentigo maligna occurs as an acquired pigmented lesion, mostly in adults older than 50 years of age.

2. It appears as a brown or black flat lesion, usually on the face, sometimes with involvement of the eyelids and conjunctiva (see subsection Primary Acquired Melanosis in section Melanotic Tumors of Conjunctiva, later), enlarging slowly in an irregular manner.

3. Approximately one-third of all lentigo maligna eventuates in malignant melanoma, noted clinically by a thickening or infiltration that elevates into a papule or nodule.

Lentigo maligna melanoma is the most common type of melanoma of the eyelid.

4. Histologically, lentigo maligna is indistinguishable from a junctional nevus. An underlying, chronic, nongranulomatous inflammatory infiltrate is common.

Nevus1

I. General information

A. A nevus is a congenital, hamartomatous tumor, flat or elevated, and usually well-circumscribed lesion.

1. It may be pigmented early in life or not until puberty or even early adulthood.

2. The nevus is composed of nevus cells that are atypical but benign-appearing dermal melanocytes.

Congenital melanocytic nevus has occurred in association with ankyloblepharon. This lesion may be explained by a failure of eyelid separation, which should occur near the 20th week of gestation.

B. Five types: (1) junctional, (2) intradermal (Fig 17.3), (3) compound (Fig. 17.4), (4) blue (Fig. 17.5), and (5) congenital oculodermal melanocytosis (nevus of Ota) (Fig. 17.6)

C. The familial atypical mole and melanoma (FAM-M) syndrome (dysplastic nevus syndrome; B–K mole syndrome)

1. The FAM-M syndrome consists of multiple, large, typical and atypical cutaneous nevi of the upper part of the trunk, buttocks, and extremities.

2. The nevi appear at an early age (usually during adolescence) and increase in number throughout life.

3. Familial cases are inherited in an autosomal-dominant pattern; sporadic cases also occur.

4. Patients who have the syndrome carry an increased risk for development of cutaneous melanomas that develop at an earlier age than in the general population.

Unlike cutaneous melanomas, ocular (conjunctival and uveal) melanocytic lesions rarely occur, and they may be no more common in patients with FAM-M syndrome than in the general population.

II. Junctional nevus

A. A junctional nevus is flat, well circumscribed, and a uniform brown color.

B. The nevus cells are located at the “junction” of the epidermis and dermis (see Fig. 17.4C).

C. The nevus has a low malignant potential.

III. Intradermal nevus (common mole; see Fig. 17.3)

A. Intradermal nevus is usually elevated, frequently is papillomatous, and is the most common type of nevus.

B. It has a brown to black color when pigmented; often, however, it is “flesh-colored.”

C. The nevus cells are entirely in the dermis.

1. The nuclei of the nevus cells tend to become “mature” (i.e., smaller, thinner or spindle-shaped, and darker) as they go deeper into the dermis. This orderly progression in structural change from superficial to deep layers is termed the normal polarity of the nevus.

2. No inflammatory cells are present unless the nevus is inflamed secondarily.

D. The nevus may be seen with proliferated Schwann elements (i.e., a neural nevus).

E. An unusual intradermal (or subepithelial) nevus is the peripunctal melanocytic nevus.

1. These involve the lower punctum, are dome-shaped and benign, and circumferentially surround the punctum, creating swollen punctal lips that result in a slitlike punctal orifice.

2. The nevus cells are subepithelial and also infiltrate the orbicularis muscle fibers.

F. Intradermal nevus probably has no malignant potential.

IV. Compound nevus (see Fig. 17.4)

A. It combines junctional and dermal components, and it is usually brown.

B. The dermal component shows a normal polarity (see Fig. 17.4; i.e., cells closest to the epidermis are larger, plumper, rounder, and paler than the deeper cells).

C. Spindle cell nevus (juvenile “melanoma,” Spitz nevus) is a special form of compound nevus that occurs predominantly in children, often as a solitary lesion on the face.

1. Histologically, it superficially resembles a malignant melanoma, but biologically it is benign.

2. It may contain spindle cells, “epithelioid” cells, and single-nucleus and multinucleated giant cells that contain abundant basophilic cytoplasm.

D. The compound nevus has a low malignant potential. The malignant melanoma arises from the junctional component.

V. Blue nevus

A. Blue nevus is usually flat and almost always pigmented from birth, appearing blue to slate-gray.

1. Combined nevus is composed of nevocellular and blue nevus constituents. A blue nevus of the tarsus comprising the predominant component of a combined nevus of the eyelid has been reported. Multifocal blue nevus has also been reported.

2. Congenital pigmented (melanocytic) nevi are arbitrarily divided into small (<3 to 4 cm), large (up to 10 cm), and giant (>10 cm). The large and giant melanocytic nevi have an approximately 8.5% chance of undergoing malignant transformation during the first 15 years of life. Most primary orbital melanomas occur in white patients and are associated with blue nevi.

B. Nevus cells are present deep in the dermis in interlacing fasciculi.

1. The cells are located deeper than junctional, dermal, or compound nevus cells.

2. The nevus cells are more spindle-shaped, more elongated, and contain larger branching processes than other types of nevus cells. They more closely resemble uveal nevus cells than do other skin nevus cells.

3. It may be very cellular [i.e., a cellular blue nevus (see Fig. 17.5), which has a low malignant potential].

C. Unless the nevus is the large or giant congenital cellular type, it has no malignant potential.

VI. Congenital oculodermal melanocytosis (nevus of Ota; see Fig. 17.6)

A. The condition can be considered a type of blue nevus of the skin around the orbit (in the distribution of the ophthalmic, maxillary, and occasionally mandibular branches of the trigeminal nerve), associated with an ipsilateral blue nevus of the conjunctiva and a diffuse nevus of the uvea (i.e., ipsilateral congenital ocular melanocytosis).

1. Skin pigmentation is usually prominent, but it may be quite subtle.

Approximately 60% of patients have the complete syndrome of skin, conjunctival, and uveal involvement (congenital oculodermal melanocytosis); approximately 34% have only skin involvement (congenital dermal melanocytosis); and approximately 6% have only conjunctival and uveal involvement (congenital ocular melanocytosis).

2. It is quite common in black and Asian patients but unusual in white patients.

3. Rarely, congenital oculodermal melanocytosis is bilateral.

4. Associated findings in the involved eye include glaucoma (which is common and may develop at any age), uveitis, and cataract.

When congenital oculodermal melanocytosis and nevus flammeus (phakomatosis pigmentovascularis) occur together, especially when each extensively involves the globe, a strong predisposition exists for the development of congenital glaucoma.

5. Melanocytosis may have a sector distribution in the choroid affecting only five to six clock hours. Nevertheless, melanoma may arise within the area of melanosis.

B. The diffuse uveal involvement causes heterochromia iridum (i.e., the involved eye is darker than the uninvolved iris).
Heterochromia iridum (see Table 17.2) is a difference in pigmentation between the two irises, as contrasted to heterochromia iridis, which is an alteration within a single iris (e.g., occasionally, ipsilateral segmental heterochromia is caused by segmental ocular involvement; the alteration of pigmentation in the single iris is properly called heterochromia iridis).

C. Congenital dermal melanocytosis may occur alone or concurrently with orbital melanocytosis, in which case it is called congenital dermal orbital melanocytosis. It may also occur concurrently with ocular melanocytosis, in which case it is called congenital oculodermal melanocytosis (nevus of Ota).

D. Congenital ocular melanocytosis (see earlier)

E. Congenital oculodermal melanocytosis is potentially malignant only when it occurs in white patients.
Malignant melanomas have been reported in the skin, conjunctiva, uvea (most common), orbit (rarely), and even in the meninges.

The lifetime prevalence of uveal melanomas in white patients who have congenital oculodermal melanocytosis has been estimated to be 1 in 400.

Malignant Melanoma

I. General information (Figs. 17.7 and 17.8)

A. From the 1960s to the 1980s, the incidence of cutaneous malignant melanoma increased 3.5-fold in men and 4.6-fold in women.

In the United States between 1973 and 1994, increases in melanoma incidence and mortality rates of approximately 121% and 39%, respectively, occurred.

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

2. An emerging epidemic of melanoma appears to be on the horizon.

B. Melanoma involves the lower lid two-thirds more often than the upper lid.

C. Associated histologic findings include solar elastosis, nevus, and basal cell carcinoma.

Rarely, a primary choroidal melanoma can occur in a patient who has had a previous cutaneous melanoma.

D. Cuticular melanomas show a nonrandom alteration of chromosome 6.

image
Fig. 17.8 Malignant melanoma of skin. A, Primary nodular malignant melanoma of skin found on back of patient shown in Fig. 17.7. Melanoma had metastasized to skin elsewhere and to both eyes. B, Biopsy shows melanoma cells in the junctional location and invading the epidermis, characteristic of primary melanoma. C and D, Gross specimens show right and left eyes removed at autopsy. Partially necrotic choroidal tumors seen. E, Pigmented melanoma cells are seen in a large vessel in the choroid. Most of the tumor cells in the choroid were necrotic. (Case referred by Drs. RC Lanciano, Jr. and S Bresalier.)

II. Malignant melanoma may arise from a pre-existing junctional, compound, or, rarely, large or giant congenital melanocytic nevus, or it may arise de novo.

III. Skin melanomas are not classified according to cell type, as are uveal melanomas.2

A. Lentigo maligna melanoma

1. The melanoma develops in a preinvasive lesion called lentigo maligna (see previously in this chapter), also called melanotic freckle of Hutchinson or circumscribed precancerous melanosis of Dubreuilh.

2. After a radial growth phase (intraepidermal spread), vertical growth phase (dermal invasion) may occur, elevating the lesion.

B. Superficial spreading malignant melanoma

1. Superficial spreading malignant melanoma has a prolonged radial growth phase before the vertical growth phase.

2. Clinically, the lesion appears as a nodule or plaque with variable pigmentation and has a “surround component” caused by the intradermal spread.

C. Nodular malignant melanoma

1. This type has only a vertical growth phase, involves the dermis early, and has the worst prognosis.

2. Clinically, the lesion appears as a nodule or plaque without a surround component because no radial growth phase occurs.

D. Acrolentiginous melanoma occurs on the palms, soles, and terminal phalanges.

E. The melanocytic neuroectodermal tumor (retinal anlage tumor, retinal choristoma) of infancy mainly involves the maxilla, but it has been reported in many other locations.

F. Mucous membrane malignant melanoma (see discussion of conjunctival melanoma, later in this chapter).
Rarely, a primary lid melanoma can occur in conjunction with an ipsilateral primary conjunctival melanoma.

G. Miscellaneous—malignant melanoma that arises in a large or giant congenital melanocytic nevus, in the central nervous system, or in the viscera

IV. Histology

A. Normal polarity is lost (i.e., the deep cells are indistinguishable from superficial cells).

B. The overlying epithelium is invaded.

If only epithelial invasion is seen, it is called a superficial spreading or incipient melanoma. Pigmentation may or may not be present. If present, it may vary in different parts of the tumor. If pigmentation is not present, the tumor is called an amelanotic melanoma.

Invasion of the underlying dermis occurs concurrently with (nodular malignant melanoma) or after (superficial spreading malignant melanoma) epithelial invasion.

C. The cells of the neoplasm are atypical.

1. The nuclear-to-cytoplasmic ratio is increased, and large abnormal cells may be seen.

2. Mitotic figures may be present, but frequently they are absent.

D. Often, an underlying inflammatory infiltrate of round cells, predominantly lymphocytes, is present.

E. Usually, a combination of the aforementioned criteria rather than any single criterion leads to the diagnosis of malignancy.

Immunohistochemical staining for versican, a major proteoglycan expressed by cutaneous malignant melanomas (CMM), may be helpful in differentiating benign melanocytic nevi (BMN), dysplastic nevi (DN), and CMM. Versican is generally negative in BMN, positive (ranging from weakly to intensively positive) in DN, and intensively positive in CMM. S-100 and NKI/C3 are helpful immunohistologic stains for determining the extent of melanocytic lesions in the conjunctiva. HMB45 immunoreactivity may be helpful in distinguishing benign from malignant melanocytic lesions, particularly those related to primary acquired melanosis (PAM).

F. Radial growth

1. Small clusters and single atypical melanocytes grow throughout the epidermis (pagetoid growth) or at the dermoepidermal junction (lentiginous growth), and they may invade the dermis in a platelike manner.

2. Corium tumor cells tend to be small and of uniform size, similar to tumor cells in the epidermis or dermoepidermal junction.

G. Vertical growth

1. Vertical differs from radial growth mainly in cytoarchitectural heterogenicity (i.e., at least some of the tumor cells in the dermis have a different appearance than those in the epidermis or at the dermoepidermal junction).

2. Mitotic figures are usually present in the dermal component.

3. Melanomas greater than 1.5 mm in depth carry a distinctly worse survival rate.

V. Prognosis

A. In general, involvement of the lid margin and conjunctiva is associated with a poorer survival rate than localization to the lid skin alone.

B. Superficial, spreading malignant melanoma has a 75% survival rate.

C. Deep malignant melanoma has a 10–39% survival rate (variability in survival rates is due to location of tumor and different authors’ statistics).

D. The level of expression of at least three integrin subunits is correlated with melanoma progression.

Melanotic Tumors of Conjunctiva

Melanocytic lesions may be found within pterygia.

Nevus

I. General information (Figs. 17.9–17.12)

A. A nevus is a hamartomatous, congenital, flat or elevated, well-circumscribed lesion that may not become pigmented until puberty or early adulthood.

1. Conjunctival nevi, most commonly found at the nasal or temporal limbus, are usually noted during the first two decades of life.

2. They are almost entirely restricted to the epibulbar surface, the plica, the caruncle (see Fig. 17.11), and the lid margin.

3. Although nevi of the tarsal conjunctiva are rare, they have been reported and comprise 3.4% of all histopathologically diagnosed conjunctival nevi.

4. Nevi are rarely located in the palpebral conjunctiva (1%), fornix (1%), or cornea (<1%).

5. Over time, a change in color may be seen in 13% of lesions, and the size may change in 8%.

B. Nevi are primarily composed of nevus cells, but they may also have epithelial elements (see later discussion of compound nevus).

C. A nevus is the most common conjunctival tumor and consists of five “classic” types:

1. Junctional

2. Subepithelial (analogous to intradermal nevus of skin)

3. Compound

4. Blue

5. Congenital melanocytosis

a. Congenital ocular melanocytosis (melanosis oculi)

b. Congenital oculodermal melanocytosis (nevus of Ota)

6. Unusual types of conjunctival nevi

II. Junctional nevus (Table 17.1; see Fig. 17.9C)

A. It is similar in appearance to junctional nevus of the skin.

B. Nevus moves with conjunctiva over sclera.

C. Histologically, nevus cells appear more “worrisome” than those of skin junctional nevi.

1. Cells tend to be larger and may reach the external surface of the epidermis.

2. The nevus cells are not necessarily limited to the junctional area of the epithelium and subepithelium but may be found within the epithelial layers, simulating invasion.

3. Histologically, the junctional nevus, when maximally pigmented, is identical in appearance to benign acquired melanosis with junctional activity.

D. Malignant potential is low.

III. Subepithelial nevus (see Table 17.1)

A. It is similar to intradermal nevus of the skin; appears flesh-colored to brown depending on the degree of pigmentation.

B. Nevus moves with conjunctiva over sclera.

C. It is not nearly as common as a junctional or compound nevus.

D. Histologically, the cells show normal polarity (i.e., smaller, darker, more spindle-shaped cells present in the deeper layers).

E. It probably has no malignant potential.

IV. Compound nevus (see Table 17.1 and Figs. 17.9D and 17.10)

A. It is quite similar to compound nevus of the skin; appears brown when pigmented.

B. Nevus moves with conjunctiva over sclera.

C. Histologically, the subepithelial component shows a normal polarity (i.e., cells found closest to the epithelium are plumper, larger, rounder, and paler).

D. The subepithelial hamartomatous component, in addition to containing nevus cells, frequently contains epithelial embryonic rests, which may develop into epithelial cysts (i.e., a cystic nevus; see Fig. 17.10).

1. The epithelial component is present in approximately 50% of conjunctival nevi.

2. Balloon cells, probably representing lipidized melanocytes, are often seen admixed with nevus cells and the epithelial component.

Rarely, balloon cell nevus may be found in children.

E. Spindle cell nevus (Spitz nevus; juvenile melanoma)

1. This special form of compound nevus occurs predominantly in children, but it may be found in adults.

2. Histologically, it is similar to “juvenile melanoma” of the skin.

F. Malignant potential is extremely low.

V. Blue nevus

A. It is quite similar to blue nevus of the skin; appears diffuse, blue to slate-gray, and is pigmented from birth.

B. It does not move with the conjunctiva over the sclera.

A junctional nevus (composed of nevocellular cells) not uncommonly may be associated with a blue nevus (composed of blue nevus cells); the two together are called a combined nevus of the conjunctiva.

C. Histologically, nevus cells, mainly deeply pigmented, are seen deep in the subepithelial tissue in interlacing fasciculi.

1. The cells are deeper than the junctional, subepithelial, or compound nevus cells, they are more spindle-shaped and elongated, and they contain larger branching processes than other types of nevus cells.

2. When very cellular, the nevus is called a cellular blue nevus.

a. It appears as a localized blue nodule.

b. It rarely becomes malignant.

D. A blue nevus may be difficult to differentiate from other lesions that cause episcleral pigmentation.

E. Only the cellular type is potentially malignant.

F. The combined nevus is composed of nevocellular and blue nevus elements (see Fig. 17.12). The nevocellular component may be pigmented or nonpigmented, and it have a junctional, subepithelial, or compound configuration.

1. The blue nevus component is composed of spindle-shaped or multipolar dendritic cells that usually have a large amount of fine pigment granules. They may demonstrate growth or be associated with “satellite” lesions.

2. The lesion may be found in children.

3. Combined nevi may involve the tarsal conjunctiva.

G. Multifocal blue nevus of the conjunctiva may simulate malignant melanoma.

VI. Congenital melanocytosis (see Table 17.1)

A. Congenital ocular melanocytosis (melanosis oculi; see Fig. 17.6)

1. Probably it is best considered as a diffuse blue nevus of the conjunctiva.

It may occur as a cellular blue nevus.

2. The condition is usually unilateral and is mainly present in dark races (blacks and Asians).

3. The lesion is blue or slate-gray from birth, and it does not move with the conjunctiva.

4. It is associated with an ipsilateral diffuse uveal nevus that causes heterochromia, which at times is subtle, especially in brown-eyed people.

Waardenburg’s syndrome consists of heterochromia iridum or iridis (unilateral or bilateral; segmental or diffuse) usually with a similar (congenital hypopigmentation) involvement of the remainder of the uvea; lateral displacement of medial canthi, combined with dystopia of the lacrimal puncta and blepharophimosis; prominent, broad root of the nose; growing together of the eyebrows with hypertrichosis of the medial portions; white forelock, a form of partial albinism (early graying of the hair begins soon after puberty); defective pigmentation in any part of the body; and congenital deafness. The involved eye is the lighter eye. The defect resides on chromosome 2q32.

5. The ocular involvement may be segmental (i.e., limited to a quadrant), and then the diffuse uveal nevus usually involves the iris, ciliary body, and choroid in the same quadrant (more or less).

6. The condition is potentially malignant when it occurs in white patients; a uveal malignant melanoma results.

Rarely, the conjunctiva or orbit may be the primary site of malignancy.

B. Congenital oculodermal melanocytosis (nevus of Ota; see previously in this chapter).

VII. Unusual types of conjunctival nevi

A. Recurrent nevus—recurrence of an incompletely excised nevus

B. Inflamed nevus—pseudoenlargement of a conjunctival nevus, secondary to inflammation, usually seen between the ages of 15 and 25 years

C. Dysplastic nevus (see previously in this chapter)

D. Spindle-cell nevus (Spitz nevus; juvenile melanoma; see previously in this chapter)

E. Balloon cell nevus—probably represents lipidized melanocytes

F. Epithelioid cell nevus—composed entirely of epithelioid melanocytes

Primary Acquired Melanosis (Figs. 17.13 and 17.14; see also Table 17.1)

I. Clinical characteristics

A. The melanosis consists of a unilateral, diffuse, brown pigmentation that moves with the conjunctiva over the sclera (analogous to lentigo maligna of the skin).

B. The mean age at diagnosis is 56 years, with 62% women and 96% whites.

1. Over 10 years, PAM may enlarge in 35% and transform to melanoma in 12%.

2. Progression to melanoma occurs in 0% of lesions lacking atypia and in 13% of PAM with severe atypia.

3. The most significant factor for both PAM recurrence and progression is the extent of PAM in clock hours.

Rarely, PAM may be amelanotic in both its benign and its malignant forms.

C. The condition has a variable and protracted course.

1. Rarely, it may remain stationary or even recede. It tends to remain benign, but it slowly enlarges over the years.

2. Approximately 17% become malignant, usually 5–10 years after onset.

D. The age of onset is approximately 40–50 years of age.

E. Rarely, PAM may be associated with malignant melanomas of the nasal cavity and paranasal sinuses.

II. Classification of unilateral PAM

A. Stage I: Benign acquired melanosis (precancerous melanosis)

1. Stage IA shows minimal melanocytic hyperplasia.

a. Hyperpigmentation of the epithelium may be the only finding (see Fig. 17.13).

b. Some increase in the number of enlarged melanocytes or a few scattered clusters of nevus cells along the basal layer may be seen.

2. Stage IB shows atypical melanocytic hyperplasia.

a. Stage IB1 shows mild to moderately severe atypical melanocytic hyperplasia (see Fig. 17.14C).

1) The lesions show enlarged melanocytes with enlarged nuclei, palisading of enlarged melanocytes along the basal layer, pagetoid “invasion” of the melanocytes into the conjunctival epithelium, and prominent nesting of melanocytes at various levels of the epithelium.

2) Histologically, it appears identical to a congenital, conjunctival, junctional nevus.

A clinical history of the age of onset is needed to differentiate between the two. Benign acquired melanosis is a clinicopathologic diagnosis, not just a pathologic diagnosis.

3. Stage IB2 shows severe atypical melanocytic hyperplasia (“in situ” malignant melanoma).

a. The lesions show mitotic activity and other cytologic features of malignancy but no invasion of the substantia propria.

b. Engorged vessels and inflammatory cells in the substantia propria are more apt to be present in stage IB2 than in stage IB1.

B. Stage II: Malignant acquired melanosis

1. Stage IIA shows superficially invasive melanoma (tumor thickness <1.5 mm; see Fig. 17.14D).

a. Minimal invasion of the substantia propria by neoplastic melanocytes is demonstrable somewhere in the lesion.

b. The condition in stages IA, IB, and IIA is analogous to superficial spreading (radial growth phase) or incipient melanoma of skin.

2. Stage IIB shows significantly invasive melanoma (tumor thickness >1.5 mm; see Fig. 17.14E). The condition in stage IIB is analogous to nodular melanoma of skin (vertical growth phase).

III. Prognosis

A. The probability for development of a stage IA lesion into a malignant melanoma is quite low.

B. The probability for development of a stage IB lesion into an invasive malignant melanoma is approximately 20% if individual atypical melanocytes are confined to the epithelial basal layer, and it is approximately 90% when they are arranged in nests or invade the epithelium in a pagetoid manner.

C. A thickness of the malignant melanoma of less than 1.5 mm (stage IIA) separates the mostly nonlethal tumors (<1.5 mm) from the very lethal tumors (>1.5 mm—stage IIB).

The terminology applied to PAM is not universally accepted, and some authors believe that the term “primary acquired melanosis with atypia” may underestimate the gravity of the lesion. Moreover, staging of associated melanomas according to the “tumor node metastasis” (TMN) system also may not correlate well with tumor extent and outcome.

IV. Causes of secondary acquired melanosis

A. Radiation

B. Metabolic disorders (e.g., Addison’s disease and pregnancy)

C. Chemical toxicity (e.g., arsenic and thorazine)

D. Chronic conjunctival disorders (e.g., trachoma, vernal conjunctivitis, keratomalacia, xeroderma pigmentosum, and acanthosis nigricans)

Primary Malignant Melanoma of Conjunctiva (Fig. 17.15; see also Fig. 17.14)

I. The incidence of primary conjunctival malignant melanoma is less than five cases per one million in the United States. The 10-year mortality is approximately 10%.

Approximately one in 20 primary conjunctival melanomas involves only the cornea (“corneally displaced conjunctival melanoma”) and has a favorable prognosis.

II. In 35–40% of cases, primary conjunctival malignant melanomas arise from junctional (rare) or compound nevi; in 25–30% of cases, they come from PAM; and in 25–30% of cases, they arise de novo or indeterminately.

A subset of conjunctival proliferations exists that cannot be classified as benign or malignant on purely cytologic criteria; these tumors should be called intermediate melanocytic proliferation of the conjunctiva.

III. Primary conjunctival malignant melanomas that arise from junctional or compound nevi are probably analogous to the cutaneous superficial spreading malignant melanoma.

IV. Primary conjunctival malignant melanomas that arise de novo or indeterminately are probably analogous to the cutaneous nodular malignant melanoma.

V. It is rare for a melanoma to arise from congenital ocular melanocytosis.

Conjunctival melanoma of an anophthalmic socket has followed radiation and chemotherapy for bilateral retinoblastoma.

VI. Conjunctival melanomas are rare in darkly pigmented people. Similarly, they are extremely rare in children.

VII. Clinical lack of pigmentation in amelanotic conjunctival melanomas may lead to delay in diagnosis.

VIII. Histology (for histology of PAM, see previously in this chapter)

A. Remnants of a conjunctival nevus may be found in or contiguous to the melanoma.

B. Normal polarity is lost (i.e., deep cells are indistinguishable from superficial cells).

C. The overlying epithelium is invaded.

Pigmentation may or may not be present. If present, it may vary in different parts of the tumor. If pigmentation is not present, the tumor is called an amelanotic melanoma.

1. Invasion of the underlying subepithelial tissue occurs concurrently with epithelial invasion.

D. The cells of the neoplasm are atypical.

1. The nuclear-to-cytoplasmic ratio is increased, and large, abnormal cells may be seen.

2. Mitotic figures may be present, but they are frequently absent.

3. The cells express S-100, tyrosinase, melan-A, HMB-45 and HMB-50 combination, and microphthalmia transcription factor at high levels. Pigment epithelium-derived growth factor can also be a useful diagnostic marker for melanocytic tumors, especially malignant melanomas.

Other immunohistochemical stains helpful in differentiating conjunctival nevus from melanoma are the antiapoptotic oncoprotein B cell leukemia/lymphoma-2 protein (Bcl-2), the tumor-suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and the heat-shock protein HSP-90: Wilms tumor gene protein (WT1) shows a graded increase in reactivity with increasing atypia in melanocytes. Fluorescence in situ hybridization (FISH) assay using probes targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1), and centromere 6 (CEP6) correlate well with the diagnosis of conjunctival melanoma.

E. Often, an underlying inflammatory infiltrate of round cells, predominantly lymphocytes, is present.

F. Silver staining of the nuclear organizer regions is helpful in determining malignancy of pigmented conjunctival lesions.

G. Usually, a combination of the aforementioned criteria rather than any single criterion leads to the diagnosis of malignancy.

Tumor-associated lymphangiogenis within conjunctival melanomas can be detected utilizing immunohistochemical stain for lymphatic vascular endothelial hyaluronan receptor-1 and podoplanin as specific lymphatic endothelial markers and Ki-67 as proliferation marker. Such lymphangiogenesis appears to be associated with an increased risk of local recurrence, lymphatic spread, distant metastasis, and melanoma-related death in conjunctival malignant melanomas.

H. Impression cytology can be helpful in the diagnosis of conjunctival lesions, particularly in amelanotic lesions. Confocal microscopy may be helpful in delineating the extent or guiding biopsy of conjunctival pigmented lesions and can support the clinical diagnosis of extrascleral extension of uveal melanoma.

Conjunctival melanomas and skin melanomas are not classified according to cell type, as are uveal melanomas. Probably most, if not all, of the “primary malignant melanomas of the cornea” arise in the limbal conjunctiva primarily and invade the cornea secondarily. Most conjunctival melanomas are most closely analogous to superficial spreading melanomas of skin. Therefore, it is not necessary to use the classification for skin melanomas for the conjunctiva.

IX. Secondary—these tumors may arise from intraocular melanomas or may be metastatic.

Rarely, a primary conjunctival malignant melanoma may extend through the anterior scleral canals to invade the eye. Differentiating between a uveal melanoma extending outward into the conjunctiva and a conjunctival melanoma invading inward to the uvea may be difficult. Removal of Bowman’s membrane at the time of an initial excision may facilitate intraocular invasion in recurrent lesions.

X. Prognosis

A. Conjunctival melanoma arising from a junctional or compound nevus has a mortality rate of approximately 20%.

B. If it arises from PAM, the mortality rate is approximately 40%.

C. If it arises de novo or its origin is indeterminate, the mortality rate is approximately 40%.

D. An accurate parameter for predicting prognosis is tumor thickness at the time of extirpation.

1. In general, if the thickness is no greater than 1.5 mm, the prognosis for life is excellent.

2. If the tumor thickness is greater than 1.5 mm, the prognosis for life is extremely grave.

Sometimes, however, even flat conjunctival melanomas may be lethal.

3. Prognosis also depends on “unfavorable” locations [i.e., the palpebral conjunctiva, fornices, plica, caruncle, and lid margins (2.2 times higher mortality rate than that for bulbar conjunctiva)].

In one series of 85 patients with conjunctival melanoma, 10-year survival rate based on tumor-related death was 77.7%. Higher local relapse rate was associated with unfavorable location (palpebral conjunctiva, fornix, caruncle, corneal stroma, and eyelid). Death from metastatic melanoma was associated with patient age older than 55 years; higher tumor, node, metastasis (TNM) category; and unfavorable tumor location.

4. When regional metastasis occurs, temporal conjunctival melanomas tend to metastasize to pre-auricular lymph nodes, and nasal conjunctival melanomas tend to metastasize to submandibular lymph nodes.

E. Patients who die of metastatic disease have significantly higher counts of cells positive for proliferating cell nuclear antigen than patients who survive a minimum of five years.

F. Adjunctive therapy for conjunctival melanoma, such as irradiation, cryotherapy, or local chemotherapy, has been suggested as a possible means to minimize local tumor recurrence.

Lesions That May Simulate Primary Conjunctival Nevus or Malignant Melanoma

I. See previous discussion of secondary acquired melanosis in this chapter.

II. See preceding discussion of secondary malignant melanoma of conjunctiva in this chapter.

III. Nevus of sclera—blue nevus, cellular blue nevus, and melanocytoma can occur in the sclera.

IV. Pseudopigmentation

A. Blue sclera (see Chapter 8)

B. Ectatic sclera lined by choroid (i.e., staphyloma) may simulate a conjunctival melanoma.

C. Scleromalacia perforans (see Chapter 8)

V. Endogenous pigmentations

A. Blood, especially its oxidation product (i.e., hemosiderin), may simulate a conjunctival melanoma.

B. Bile

1. In acute icterus, bilirubin is deposited predominantly in the conjunctiva, not in the sclera.

2. With chronic, long-standing icterus, the bilirubin, although mainly in the conjunctiva, is also deposited in the sclera.

VI. Metabolic disorders

A. Ochronosis (alkaptonuria; see Chapter 8)

B. Gaucher’s disease shows conjunctival changes consisting of pigmented, triangular, brown pingueculae that contain Gaucher’s cells. They appear in the second decade of life.

VII. Exogenous pigmentations

A. Epinephrine plaques (see Chapter 7)

B. Argyrosis (see Fig. 7.10)

Ocular argyrosis may occur secondary to the chronic self-application of eyelash tint. Silver deposition from this mechanism may be relatively extensive and involve the lid margin, caruncle, and conjunctiva as well as the eyelid.

C. Mascara

D. Industrial hazards (e.g., quinones and aniline dyes)

E. Iron

F. Foreign bodies

VIII. Pigment spots of the sclera (Fig. 17.16)

A. Pigment spots of the sclera are most commonly found with darkly pigmented irises.

B. They consist of episcleral collections of uveal melanocytes 3 or 4 mm from the limbus and are always associated with a perforating anterior ciliary vessel, an intrascleral nerve loop of Axenfeld, or both.

C. They decrease in frequency from superior to inferior to temporal to nasal quadrants.

D. The conjunctiva is freely movable over the pigment spot.

E. The associated intrascleral nerve loop remains painful to touch even after local instillation of a topical anesthetic.

F. Pigment spots of the sclera may be confused with conjunctival nevi, melanomas, and foreign bodies (see Fig. 17.16).

IX. Pigmented squamous cell carcinoma of the conjunctiva may simulate malignant melanoma.

Melanotic Tumors of Pigment Epithelium of Iris, Ciliary Body, and Retina

The ultrasound biomicroscope (UBM) and similar devices are particularly useful in the evaluation of anteriorly located melanotic uveal and pigment epithelial tumors. UBM can be helpful in therapeutic planning and follow-up following treatment for such tumors.

Reactive Tumors

I. Congenital (see Fig. 9.10)

A. Solid and cystic proliferation of the iris PE, especially the PE near the iris root, is a frequent congenital anomaly.

Although congenital, the anomaly may not be noted clinically until adult life. Most primary cysts of the iris PE have a benign clinical course that rarely necessitates treatment.

1. The PE may break off and float freely in the anterior chamber or lodge in the anterior chamber angle, where it may be pigmented or clear and transparent.

Indications for surgical removal of such cysts include rapid enlargement or significant reduction in endothelial cell count. Visual symptoms from primary pupillary epithelial cysts have also necessitated cyst removal. Cysts in that location usually have an autosomal-dominant inheritance pattern, with occasional lack of penetrance.

2. It may simulate a malignant melanoma of the anterior ciliary body. Conversely, cavitary melanoma simulating a cyst is an uncommon presentation for ciliary body melanoma.

3. It may result from intrauterine inflammation, trauma, or unknown causes.

4. Iris pigment epithelial cysts must be considered in the differential diagnosis of angle closure glaucoma in teenagers.

5. Histologically, the PE proliferates in cords, tubes, or cystic structures.

6. Primary cysts of the iris stroma arise within the stroma and are lined by nonkeratinized squamous epithelium and not by iris pigment epithelium (Fig. 17.17). In contrast, as the name implies, cysts of the posterior epithelium are lined by iris pigment epithelium.

B. Congenital simple hamartoma of the RPE is usually a black, full-thickness mass, often adjacent to the fovea. Vision is usually well preserved.

C. Combined hamartoma (idiopathic reactive hyperplasia) of the retina and retinal PE (Fig. 17.18)

1. The lesion is mainly juxtapapillary but may be located peripherally.

The differential diagnosis includes cavernous hemangioma, capillary hemangioma (von Hippel’s disease), astrocytic hamartoma (tuberous sclerosis), melanocytoma, malignant melanoma, choroidal osteoma, and retinoblastoma.

2. It is mostly seen in young men between the ages of 20 and 45 years (range, 12–63 years).

It is not known whether these lesions are congenital or reactive, but they are probably congenital.

3. Clinically, the lesion usually appears as a solitary grayish mass with variable pigmentation and vascularity.

a. Retinal contracture and subsequent impairment of vision (if the macula is involved) may occur, but only rarely is growth noted.

b. Atypical findings include subneural retinal hemorrhage, fluid accumulation, and neovascularization; intraneural retinal cystic spaces; arterioarterial anastomoses; vitreous hemorrhage; and inner-layer neural retinal holes in acquired retinoschisis.

c. Combined hamartoma may also be associated with retinal capillary nonperfusion and preretinal neovascularization presumably indicating associated retinal ischemia.

d. An association may exist between neurofibromatosis type-1 and combined hamartoma of the retina and retinal pigment epithelium (RPE). Combined hamartoma of the retina and RPE has been associated with juvenile nasopharyngeal angiofibroma and has been reported involving the optic disc associated with choroidal neovascularization.

Combined hamartoma of the retina and RPE may be indistinguishable from congenital RPE malformation or congenital simple hamartoma of the RPE. Congenital RPE malformation consists of RPE hypertrophy (not hyperplasia, as in the hamartoma) and abnormalities of the retina such as thickening, vascular tortuosity, and retinal capillary abnormalities. Congenital simple hamartoma of the RPE (also called RPE hamartoma, congenital or primary RPE hyperplasia, and congenital RPE adenoma) appears in the macula as a darkly pigmented, nodular mass involving full-thickness retina and containing sharp margins. Rarely, congenital simple RPE hamartoma may occur in the central fovea and result in poor vision. Optical coherence tomography can be helpful in the evaluation of such lesions.

4. Histologically, combined hamartoma of the retina and RPE consists of an intraneural retinal proliferation of RPE associated with abnormal (hamartomatous) retinal blood vessels, and areas of dysplastic retina.

A 10-year-old girl with branchio-oculofacial (BOF) syndrome has been reported with an iris pigment epithelial cyst of the right eye and a combined hamartoma of the retina and RPE. BOF syndrome is characterized by mild to severe craniofacial, auricular, oral, and ocular anomalies. The case reported also displayed lacrimal sac fistulas and orbital dermoid cyst.

D. Medulloepithelioma (diktyoma)

1. Medulloepithelioma is a unilateral, solitary ocular tumor.

a. It arises from the ciliary epithelium as a well-circumscribed mass, or it may infiltrate the area around the lens.

Rarely, the tumor can arise from the iris or optic nerve in the region of the optic disc.

b. Usually, it presents during the first decade with a peculiar pupillary reflex, a characteristic lens notch and lens subluxation, and a tendency to cause a neoplastic cyclitic membrane and a secondary neovascular glaucoma.

Even more rarely, medulloepithelioma may present as a pigmented ciliary body tumor, instead of the usual fleshy pink appearance.

c. The tumor grows slowly and is only locally aggressive.

Echographic findings of a highly reflective, irregularly structured tumor with associated cystic changes involving the ciliary body region may help establish the diagnosis of medulloepithelioma.

d. Glaucoma may be the presenting sign.

e. Delay in diagnosis is common.

2. Medulloepithelioma (nonteratoid medulloepithelioma) may be benign (Fig. 17.19) or malignant.

3. Heteroplastic elements may be present, in which case the tumor is termed a teratoid medulloepithelioma, benign or malignant (Fig. 17.20).

4. Histologically, nonteratoid medulloepithelioma consists of poorly differentiated neuroectodermal tissue that in some areas resembles embryonic retina.

a. The cells are frequently arranged in a double layer, and the innermost layer secretes hyaluronic acid (“vitreous”).

When heteroplastic elements are present [e.g., cartilage is present in 20% of cases; the tumor may also contain rhabdomyoblasts (see Figs. 17.20B and 17.20C), which are large globular cells that resemble ganglion cells], it is called a teratoid medulloepithelioma.

b. The neuroepithelial cells are positive for neuron-specific enolase, vimentin, and often S-100 protein.

c. The neuroblastic cells are usually positive for neuron-specific enolase and synaptophysin.

Nonteratoid and teratoid medulloepithelioma, unlike retinoblastoma, appears to be a truly multipotential tumor.

d. Malignant nonteratoid tumors contain tightly packed neuroblastic cells that sometimes show marked mitotic activity and resemble retinoblastoma cells.

e. Malignant teratoid tumors often have sarcomatous changes in one or more of the heteroplastic elements (e.g., rhabdomyosarcoma or chondrosarcoma).

Rarely, a congenital malignant teratoid tumor can involve both the eye and the orbit.

II. Drusen (see Chapter 11)

III. Pseudoneoplastic proliferations

A. Pupillary—after miotic therapy (phospholine iodide for childhood accommodative esotropia), the iris PE may enlarge or proliferate into the pupillary area.

B. Intraneural retinal (usually from RPE)

1. Intraneural retinal reactive RPE proliferations may occur in abiotrophic diseases such as retinitis pigmentosa (see Fig. 11.36).

In retinitis pigmentosa, the pigmented cells surrounding the blood vessels (“bone–corpuscular” pigmentation) may be pigment-filled macrophages, Müller cells, or migrated RPE cells.

2. Pseudoneoplastic proliferations may also occur in metabolic disorders such as homocystinuria; after trauma; as a senile change, especially in the region of the macula; after ocular inflammation; or in long-standing diabetes.

3. Ringschwiele or demarcation line (see Chapter 11)

4. Focal hyperplasia of the RPE can produce tumors that invade and replace the overlying sensory retina.

RPE proliferation through a stage IV macular hole can simulate a retinal pigment epithelial neoplasm.

5. Optical coherence tomography can be helpful in evaluating RPE changes secondary to choroidal metastasis of nonocular tumors and for their follow-up after treatment.

C. Intravitreal (usually from ciliary PE or RPE, but may be from iris PE)

1. Intravitreal pseudoneoplastic proliferations of the PE are most common after trauma.

2. They may follow purulent endophthalmitis or other ocular inflammations.

3. Histologically, proliferated epithelium, pigmented and nonpigmented, extends out in cords and sheets, surrounded by abundant basement membrane material.

D. Pseudoepitheliomatous hyperplasia of the ciliary body epithelium

May simulate a malignant melanoma

Pigmented iris and choroidal lesions have been found with cataracts and progressive nummular retinal pigment epithelial lesions, and progressive visual loss in association with uterine cancer.

IV. Metaplastic

A. Disciform degeneration of the macula (i.e., macular scarring in age-related macular degeneration) represents fibrous metaplasia of the RPE.

B. Bone formation (osseous metaplasia; see Fig. 3.14)

1. It is not certain if the PE undergoes osseous metaplasia or acts as an inducer for surrounding mesenchymal tissue to undergo osseous metaplasia.

2. Intraocular osseous metaplasia is not preceded by cartilage formation.

3. It is common after trauma, long-standing uveitis, and endophthalmitis.

V. Atrophic changes other than as part of age-related macular degeneration.

A. Green laser-induced retinopathy can result in a yellowish discoloration at the level of the RPE and RPE damage noted on histopathologic examination.

B. Nummular changes at the level of the RPE may be found in bilateral diffuse uveal melanocytic proliferation (BDUMP) syndrome, in which uveal melanocytic proliferation is usually the main finding (see also later).

Nonreactive Tumors

I. Congenital

A. Glioneuroma (Fig. 17.21)

1. Glioneuromas are rare, benign, choristomatous tumors.

2. Histologically, the tumor is composed of only brain tissue, containing neurons and glial cells and lacking the embryonic retina, ciliary epithelium, and primitive vitreous found in medulloepitheliomas.
Immunohistochemistry shows positivity in the neuronal cells for neuron-specific enolase, synaptophysin, and neurofilaments; in the glial cells for vimentin, glial fibrillary acidic protein, and S-100 protein; and in the neuroepithelial cells for cytokeratins, vimentin, neuron-specific enolase, and S-100 protein (suggesting ciliary epithelial origin).

B. Grouped pigmentation (bear tracks; Fig. 17.22; see Chapter 11)

C. RPE hypertrophy (melanotic RPE nevus; benign “melanoma” of the RPE of Reese and Jones; see Fig. 17.22)

D. Congenital hypertrophy of the RPE (CHRPE) presents clinically as a round or oval, jet-black, flat (or slightly elevated) lesion usually surrounded by a halo (due to partial or complete RPE hypopigmentation), most commonly found in the temporal fundus.

1. It may contain “punched-out,” yellow, depigmented patches of irregular sizes and shapes, called lacunae.

2. The depigmentation tends to enlarge or coalesce or both in approximately 80% of lesions and may lead to total depigmentation, leaving a recognizable, round or oval, well-circumscribed, orange hypopigmented or white (albinotic) amelanotic lesion.

3. Often, scotomata are found, corresponding to neural retinal photoreceptor degeneration overlying the lesion.

The lesions may show enlargement over time, especially with lacunae formation and expansion. In some lesions, overlying retinal vascular changes can be demonstrated by fluorescein. The combination of CHRPE and abnormalities of the retina (such as a thickened retina, tortuosity of retinal vessels, and dilated abnormal capillaries) is called congenital RPE malformation.

4. CHRPE, a congenital lesion that has been found in a newborn, can be divided into three forms: solid, grouped, and multiple. Bilateral or multiple CHRPE lesions can be associated with Gardner’s syndrome.

5. CHRPE may be associated with familial adenomatous polyposis (FAP) of the colon and the variant, Gardner’s syndrome.

a. CHRPE is present in 70% of families with FAP.

b. FAP has a 100% incidence of colonic adenocarcinoma if untreated.

c. In addition to CHRPE, FAP may have extracolonic manifestations, such as osteomas, dental abnormalities, desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts, and central nervous system).

6. The common CHRPE, not associated with FAP, is described as generally round, can have scalloped borders, and may have depigmented lacunae or be totally depigmented. In contrast, FAP-associated lesions are extremely pleomorphic in shape (round, pencil-shaped, coffee bean-shaped, or other with a tail of depigmentation at one end).

7. Gardner’s syndrome consists of FAP associated with skull and mandible osteomas; dental abnormalities; and fibromas on the scalp, shoulders, arms, and back.

A variant of this autosomal-dominant disorder is Turcot’s syndrome (glioma–polyposis), which consists of FAP and neuroepithelial tumors of the central nervous system. Multiple regions of hamartomas of the RPE may be found on examination of the ocular fundi.

8. Hamartomas of the RPE are divided into at least three types: (1) a monolayer of hypertrophic RPE cells (CHRPE), (2) a mound of pigmented cells interposed between Bruch’s membrane and RPE basement membrane, and (3) a small mound of hyperplastic RPE cells (nodular RPE hypertrophy).

a. Hamartomas of the RPE are most helpful in the diagnosis of Gardner’s syndrome.

b. Hamartomas of the RPE are detectable before the development of intestinal polyps.

c. The presence of four or more hamartomas of the RPE is a highly specific phenotypic marker for Gardner’s syndrome.

d. One or more genes on chromosome 5q21 in the adenomatous polyposis coli (APC) gene are important for the development of colorectal cancers associated with FAP and its variant, Gardner’s syndrome.

The location of the mutation determines the expression of the severity of FAP and the degree to which CHRPE and other extracolonic manifestations are expressed. So-called “attenuated” FAP (with <100 colorectal adenomas) is correlated with mutations before codon 157, after codon 1595, and in the alternatively spliced region of exon 9. Severe polyposis (>1000 adenomas) is present in patients with mutations between codons 1250 and 1464. Mutations in the remainder of the APC gene cause an intermediate phenotype with hundreds to thousands of adenomas. Moreover, CHRPE and desmoid tumors are associated with mutations between codons 311 and 1444 and after codon 1444, respectively.

e. There is no association between CHRPE characteristics and specific FAP variants.

9. Clinically, bilateral lesions and lesions with a depigmented halo are the hallmarks of CHRPE associated with FAP. Patients with isolated CHRPE and those with grouped pigmentation are not associated with FAP. It is stated that the combination of genetic analysis and fundus examination offers a 100% diagnostic predictability for FAP.

10. Histologically, CHRPE consists of hypertrophy of RPE cells and an increase in size (macromelanosomes) and number of their melanin granules.

Although RPE hypertrophy (increase in size of cells) is the predominant component, RPE hyperplasia (increase in number of cells) is also present in many lesions.

a. The surrounding halo is due to atrophy or loss of pigment from the adjacent RPE or both.

b. Degeneration of the overlying neural retinal photoreceptor cells may be found.

The histology of CHRPE is almost identical to that of grouped pigmentation (bear tracks—see Chapter 11). Both can be considered variants of the same process. The former is a larger focal lesion, and the latter are smaller multifocal lesions.

11. Congenital hypertrophy of the RPE can give rise to adenocarcinoma.

A Vogt–Koyanagi–Harada-like syndrome accompanied by retinal pigment epithelial hypopigmentation may accompany successful tumor-infiltrating lymphocyte immunotherapy for metastatic melanoma.

Acquired Neoplasms

I. Fuchs’ adenoma (proliferation rather than neoplasm; see Fig. 9.17)

II. Adenoma (epithelioma; Fig. 17.23)

A. Adenomas may arise from the ciliary epithelium or RPE.

B. Clinically, they tend to be darker and their margins more abruptly elevated than in ciliary body melanomas.

Adenoma of the ciliary body nonpigmented epithelium has been reported with concomitant neovascularization of the optic disc (NVD) and cystoid macular edema (CME). It was postulated that elevated vascular endothelial growth factors in intraocular fluids, which were determined in both aqueous and vitreous obtained at surgery, may have played a role in the development of NVD and CME.

C. Benign adenoma of the ciliary body pigment epithelium may exhibit progressive growth and undergo malignant change. These lesions may invade the anterior chamber angle or cause pigment dispersion. Cataract, vitreous hemorrhage, and neovascular glaucoma have also been reported in association with these lesions.

D. Histologically, the epithelial cells appear polyhedral and have variable pigmentation.

1. They may show a tubular (papillary) pattern, a vacuolated (solid) pattern, or a mixture of both; the tumors may become cystic.

2. The heavily pigmented cells are frequently vacuolated.

3. Nuclear atypia is common, but mitotic figures are rare.

4. Immunohistochemically, they show positivity for vimentin, S-100 protein, and low-molecular-weight cytokeratins. They are negative for vimentin.

5. In contrast to tumor-like hyperplastic lesions of the RPE, the RPE adenoma is sporadic melan-A-positive.

6. Histologically, adenoma may be difficult to differentiate from reactive proliferations of the PE.

The cells of the adenoma are variably pigmented and are packed together tightly with little or no stroma, whereas the individual cells in pseudoadenomatous hyperplasia tend to be separated by an amorphous basement membrane-like material and show little atypia and no mitotic figures.

7. Immunohistochemistry of retinal pigment epithelial adenoma demonstrates that the tumor is positive with S-100, neuron-specific enolase, synaptophysin, epithelial membrane antigen, and vimentin staining. The tumors are negative for melanoma-specific antigen HMB45 and cytokeratin.

8. Transmission electron microscopy reveals tight junctions between cells.

III. Adenocarcinoma

A. Like adenomas, pleomorphic adenocarcinomas may have a vacuolated (solid) or tubular (papillary) pattern or a mixture of both.

B. When the PE becomes malignant, it forms an incidentally pigmented adenocarcinoma, not a malignant melanoma.

Clinically, the tumors are locally invasive, but it is questionable whether they have the biologic ability to metastasize or even to undergo extrascleral extension.

C. Adenocarcinoma is a histologic diagnosis based on cellular atypia.

1. In addition to hyaluronic acid secretion, immunohistochemical staining shows strong positivity for vimentin, focal positivity for epithelial basement membrane antigen and S-100 protein, and weak positivity for neuron-specific enolase.

2. Adenocarcinoma of the nonpigmented ciliary epithelium has been reported to be immunohistochemically positive for AE1 and epithelial membrane antigen.

An imbalance of chromosome 6 has been found by comparative genomic hybridization in a patient with pleomorphic adenocarcinoma of the ciliary epithelium.

IV. Leiomyoepithelioma of iris PE

V. Melanotic neuroectodermal (retinal anlage) tumor of infancy

Melanotic Tumors of the Uvea

Iris

I. Ephelis (freckle; Fig. 17.24)

A. A freckle shows increased pigmentation of anterior border layer melanocytes without increased number of melanocytes.

B. There is no discrete mass or nodule.

II. Nevus (see Fig. 17.24)

A. A nevus shows an increased number of atypical, benign-appearing melanocytes (i.e., nevus cells) with variable pigmentation.

B. A discrete mass or nodule is present, often on the iris anterior surface (i.e., within the anterior border layer of the iris).

C. An increased incidence of iris nevi occurs in people who have neurofibromatosis (see Fig. 2.4) but probably not in those who have ciliary body or choroidal malignant melanomas.

D. A diffuse (or rarely segmental) nevus of the iris (and the rest of the uvea) is present in congenital ocular or oculodermal melanocytosis.

Rarely, a diffuse nevus of the iris can cause glaucoma by direct involvement of the drainage area or by synechiae and secondary closed-angle glaucoma.

E. An acquired, diffuse nevus of the iris may be associated with the iris nevus syndrome, part of the iridocorneal endothelial (ICE) syndrome (see Chapter 16).

Melanocytoma (magnocellular nevus; see later in this chapter) of the iris may occur. Necrosis of a melanocytoma may mislead the clinician to a diagnosis of malignant melanoma. Another unusual type of iris nevus is called the benign epithelioid cell nevus. A rare case of probable autosomal-dominant, “aggressive” iris nevus in childhood has been reported.

F. Malignant change is rare.

III. Heterochromia (Table 17.2)

IV. Malignant melanoma (Figs. 17.25 and 17.26; see also Fig. 16.18)

A. Iris malignant melanomas have no sex predilection; the average age of involvement is 64 years.

Pediatric cases are very uncommon and comprise 8% of iris melanomas. In general, pediatric cases have smaller tumor size, less tumor seeding in the angle, and lower incidence of secondary glaucoma.

B. They are the most common primary malignant neoplasm of the iris and constitute approximately 5–8% of all uveal melanomas; they usually arise from the anterior border layer tissue of the iris (as do iris nevi).

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