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

E

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.

b). 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.

2). 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 IB2 than IB1.

A

C

2.Stage II: Malignant acquired melanosis

a.Stage IIA shows superficially invasive melanoma

(tumor thickness <1.5 mm; see Fig. 17.13D).

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

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

b.Stage IIB shows significantly invasive melanoma (tumor thickness >1.5 mm; see Fig. 17.13E). The condition in stage IIB is analogous to nodular melanoma of skin (vertical growth phase).

3.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 approximately 90% when they are arranged in nests or invade the epithelium in a pagetoid fashion.

c.A thickness of the malignant melanoma of less than 1.5 mm (stage IIA) separates the mostly

B

Fig. 17.14 Malignant melanoma. A, A pigmented conjunctival lesion near the limbus, present since childhood, had undergone recent rapid growth. B, A histological section of an incomplete excisional biopsy shows a heavily pigmented tumor. C, A bleached section shows a loss of normal polarity (i.e., the cells deep in the lesion are of the same size as those nearer the surface instead of being smaller). Usually, conjunctival melanomas not thicker than 1.5 mm have an excellent prognosis, whereas those thicker than 1.5 mm have a grave prognosis.

nonlethal tumors (<1.5 mm) from the very lethal tumors (>1.5 mm—stage IIB).

II.Causes of secondary acquired melanosis*

A.Radiation

B.Metabolic disorders

1.Addison’s disease

2.Pregnancy

C.Chemical toxicity

1.Arsenic

2.Thorazine

D.Chronic conjunctival disorders

1.Trachoma

2.Vernal conjunctivitis

3.Keratomalacia

4.Xeroderma pigmentosum

5.Acanthosis nigricans

Malignant Melanoma

I.Primary (Fig. 17.14; see also Fig. 17.13)

A.The incidence of primary conjunctival malignant melanoma is less than 5 cases per million in the United

States. The 10-year mortality is about 10%.

*Modified from Henkind P, Friedman AH: External ocular pigmentation.

Int Ophthalmol Clin 11:87, 1971.

About 1 in 20 primary conjunctival melanomas involve only the cornea (“corneally displaced conjunctival melanoma”), and have a favorable prognosis.

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

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

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

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

F.Melanomas are rare in black people.

G.Histology (for histology of PAM, see pp. 680–681 in this chapter)

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

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

3.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.

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

4.The cells of the neoplasm are atypical.

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

b.Mitotic figures may be present, but are frequently absent.

c.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 a useful diagnostic marker for melanocytic tumors, especially malignant melanomas.

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

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

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

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. It is not necessary, therefore, to use the classification for skin melanomas for the conjunctiva.

II.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.

III.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, however, 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 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 greater than 55 years, higher tumor, node, metastasis (TNM) category, and unfavorable tumor location.

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 5 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 earlier 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 p. 314 in Chapter 8)

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

C.Scleromalacia perforans (see p. 317 in 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 depos-

ited in the sclera. VI. Metabolic disorders

A.Ochronosis (alkaptonuria; see p. 314 in 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 p. 235 in Chapter 7)

B.Argyrosis (see Fig. 7.10)

Ocular argyrosis may occur secondary to the chronic selfapplication 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

1.Quinones

2.Aniline dyes

E.Iron

F.Foreign bodies

VIII. Pigment spots of the sclera (Fig. 17.15)

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

B.They consist of episcleral collections of uveal melanocytes 3 to 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. 17.15).

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 followup 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 o 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 di erential diagnosis of angle closure glaucoma in teenagers.

5.Histologically, the PE proliferates in cords, tubes, or cystic structures.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. 17.16)

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 to 63 years).

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

b.Rarely, growth is documented.

c.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.

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

e.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 (hamar-

tomatous) 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 wellcircumscribed 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.

2.Medulloepithelioma (nonteratoid medulloepithelioma) may be benign (Fig. 17.17) or malignant.

3.Heteroplastic elements may be present, in which case the tumor is termed a teratoid medulloepithelioma, benign or malignant (Fig. 17.18).

4.Histologically, nonteratoid medulloepithelioma consists of poorly di erentiated 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 Fig. 17.18B and C), which are large globular cells that resemble ganglion cells], it is called a teratoid medulloepithelioma.

b.The neuroepithelial cells are positive for neuronspecific 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 p. 425 in 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, e.g., 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 p. 469 in Chapter 11)

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

5.Optical coherence tomography can be helpful in evaluating RPE changes secondary to choroidal metastasis of nonocular tumors and for their followup 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

1.May simulate a malignant melanoma

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 di use uveal melanocytic proliferation (BDUMP) syndrome in which uveal melanocytic proliferation is usually the chief finding (see also below).

Nonreactive Tumors

I.Congenital

A. Glioneuroma (Fig. 17.19)

1.Glioneuromas are rare, benign, choristomatous tumors.

2.Histologically, the tumor is composed only of brain tissue, containing neurons and glial cells and lacking the embryonic retina, ciliary epithelium, and primitive vitreous found in medulloepitheliomas.

a.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. 17.20; see also p. 396 in Chapter 11)

C.RPE hypertrophy (melanotic RPE nevus; benign

“melanoma” of the RPE of Reese and Jones; see Fig. 17.20)

1.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).

The lesions may show enlargement over time, especially with lacunae formation and expansion.

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

b.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.

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

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.

d.CHRPE can be divided into three forms: solid, grouped, and multiple; bilateral or multiple can be associated with Gardner’s syndrome.

2.It is a congenital lesion and has been found in a newborn.

3.CHRPE may be associated with familial polyposis of the colon (Gardner’s syndrome).

a.Gardner’s syndrome consists of familial adenomatous polyposis (FAP), which has an auto- somal-dominant inheritance pattern, and

extracolonic manifestations, including hamartomas of the RPE, osteomas, epidermoid cysts, desmoid tumors, and infrequent malignant tumors of liver, thyroid, brain, and other organs.

b.In Slovakia, mutations within codons 1309 and

1060 were associated with a large number of colorectal polyps and CHRPE. Individuals with adenomatous polyposis and CHRPE, but lacking mutations in the adenomatous polyposis coli (APC) gene in patients in Hong Kong, suggest that these disorders can result from abnormalities not associated with APC coding region mutations.

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.

1). In patients with FAP, over 100 adenomatous colorectal polyps develop before early adulthood.

Fig. 17.19 Glioneuroma. A, Tumor in region of ciliary body, removed by iridocyclectomy, extends into iris root. B, Tumor shows tissue similar to brain tissue, containing ganglion cells; shown with increased magnification in C. (Case presented by Dr. DJ Addison at Meeting of the Association of Ophthalmic Alumni of the Armed Forces Institute of Pathology, Washington, DC, 1977.)

Without treatment, adenocarcinoma always develops.

2). Hamartomas of the RPE are divided into at least three types: a monolayer of hypertrophic

RPE cells (CHRPE); a mound of pigmented cells interposed between Bruch’s membrane and RPE basement membrane; and a small mound of hyperplastic RPE cells (nodular RPE hypertrophy).

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

1). Hamartomas of the RPE are detectable before the development of intestinal polyps.

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

c.One or more genes on chromosome 5q21 are important for the development of colorectal cancers associated with FAP.

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