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.

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)

I. An ephelis (freckle) is a brown, circumscribed macule normally only found on areas of skin exposed to sunlight.

II. The color is due to increased pigmentation in the basal cell layer of the epidermis. The pigment (melanin) is derived from hyperactive melanocytes that “secrete” their pigment into epidermal basal cells.

III. The melanocytes are fewer in number but larger and more functionally active than those in adjacent, surrounding, paler epidermis.

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.

Fig. 17.2 Lentigo maligna (Hutchinson’s freckle). A, Clinical appearance of acquired pigmented lesion of the left lower lid. B, Histologic section shows nevus cells in the junctional location, indistinguishable from a junctional nevus. (Case presented by Dr. VB Bernardino, Jr. to the meeting of the Eastern Ophthalmic Pathology Society, 1975.)

Nevus ¹

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)

Fig. 17.3 Intradermal nevus. A, Large, deeply pigmented nevus at lid margin. B, Nests of nevus cells fill the dermis except for a narrow area just under the epithelium; shown with increased magnification in C. C, The nuclei of the nevus cells become smaller, thinner or spindle-shaped, and darker as they go deeper into the dermis (i.e., they show normal polarity).

Fig. 17.4 Compound nevus. A, Moderately pigmented nevus at lid margin. B, Histologic section shows nevus cells at junction of epidermis and dermis as well as in dermis. C, Increased magnification demonstrates nevus cells in junctional and dermal locations.

Fig. 17.5 Cellular blue nevus. A, Nevus involves lids, conjunctiva, and orbit. B, Histopathologic section of partially removed tumor shows nonpigmented and pigmented nevus cells in the deepest dermis. C, Another area shows nonpigmented and pigmented nevus cells involving orbital fat. D, Increased magnification of another region shows nonpigmented and pigmented dendritic nevus cells that contain abundant cytoplasm and small spindle nuclei. (Case presented by Dr. WC Frayer to the meeting of the Eastern Ophthalmic Pathology Society, 1975.)

Fig. 17.6 Congenital oculodermal melanocytosis (nevus of Ota). A, Heterochromia iridum present; left iris darker than right. Slate-gray pigmentation of sclera is seen inferiorly in the left eye. Note hyperpigmentation of skin around left eye. Another patient who had congenital oculodermal melanocytosis in the left eye shows a normal-colored right (B) but a much darker left (C) fundus. D, Diffuse, maximally pigmented nevus cells fill the choroid, which is characteristic of the uveal lesion in congenital ocular melanocytosis.

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.

Fig. 17.7 Malignant melanoma of skin. A (OD) and B (OS), Patient presented with bilateral pigmented choroidal tumors. C, Same patient shows multiple pigmented skin tumors. D, Biopsy of skin tumor shows melanoma cells in dermis, sparing the junctional and epithelial locations, characteristic of metastatic melanoma—see Fig. 17.8. (Case referred by Drs. RC Lanciano, Jr. and S Bresalier.)

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).