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Intraocular Tumors in Adults



Intraocular Tumors in Adults





MELANOCYTIC TUMORS OF THE UVEAL TRACT


Introduction

In adults, most intraocular tumors arise from, or involve the uveal tract, the eye’s middle coat composed of the stroma of the iris, ciliary body, and choroid. The uvea tract is highly vascular and pigmented. The pigment is contained within the cytoplasm of dendritic uveal melanocytes, which are derived embryologically from the neural crest (Fig. 11-1). A similar number of uveal melanocytes are present in lightly and heavily pigmented eyes. Increasing intensity of uveal pigmentation (and eye color) is caused by a corresponding increase in the size and number of melanin pigment granules or melanosomes in the cytoplasm of the melanocytes. The pigment may protect against the development of uveal tumors, because uveal malignant melanoma occurs most often in patients with blue eyes and is rare in heavily pigmented individuals.

The choroidal vessels occasionally undergo hamartomatous proliferation forming hemangiomas, and the rich vascular supply of the posterior choroid explains that region’s predilection for blood-borne metastases.


NEVI

Uveal nevi are benign melanocytic neoplasms that are incapable of metastasis. Nevi, which occur in 5% of adults, are the most common intraocular tumor. Most choroidal nevi typically appear as flat or minimally elevated patches of increased choroidal pigmentation that measure 1 to 2 mm in diameter and are <2 mm in thickness (Fig. 11-2A). They may be pigmented or amelanotic, and they often have an irregular or feathery border. Drusen often develop on the surface of nevi with time and are one of the factors that serve to distinguish them from small melanomas. Although they are considered stationary lesions, about one third show slight enlargement when followed for many years. About 8% of nevi are classified as giant, measuring more than 10 mm in diameter. Signs of chronicity such as drusen serve to distinguish them from melanomas. Halo nevi are a variant that have a brown center and a yellow halo. Nevi occasionally undergo malignant transformation into malignant melanoma; the rate of malignant transformation is estimated to be only 1/10,000 to 15,000 per year.






FIG. 11-1. A. Choroid. The choroid is the posterior part of the uveal tract. Its stroma contains dendritiform melanocytes and vessels. The latter include the choriocapillaris, which is located directly beneath the Bruch membrane and Sattler and Haller layers composed of progressively larger vessels. B. Scanning electron micrograph shows dendritic configuration of a choroidal melanocyte. (A. H&E × 100, B. SEM ×1250.)

It may be difficult to differentiate between a choroidal nevus and a small malignant melanoma clinically. Detecting melanomas when they are small is important because it has been reported that each millimeter increase in the thickness of a melanoma results in approximately a 5% increased risk for metastatic disease at 10 years. The observation of tumor growth may be the only clinical criterion that is helpful in this regard. Dr. Carol Shields and her team on the Oncology Service at the Wills Eye Hospital identified certain clinical tumor parameters that suggest that pigmented lesion will grow and probably is a melanoma that should be treated. The mnemonic “To Find Small Ocular Melanoma Using Helpful Hints Daily” includes these parameters. The initial “T” denotes thickness greater than 2 mm, “F” the presence of subretinal fluid,
“S” symptoms, “O” orange pigment on the surface of the tumor and “M” the location of the posterior margin of the tumor less than 3 mm from the optic disc. The remainder of the mnemonic refers to an acoustically hollow appearance on B scan ultrasonography and the absence of a halo and drusen. A small melanocytic lesion of the choroid with none of these factors has a 3% risk of growth into melanoma at 5 years and most likely represents a choroidal nevus. Tumors that display one factor have a 38% risk of growth, and those with two or more factors show growth in over 50% of cases. Most tumors with two or more risk factors probably represent small choroidal melanomas, and early treatment generally is indicated.






FIG. 11-2. Choroidal nevus. A. Small pigmented lesion presumed to be nevus remained stable on follow-up. B. Choroidal nevus. Choroid contains infiltrate of pigmented spindle cells with bland nuclei. The RPE and choriocapillaris are intact and the overlying retina remains attached. (B. H&E ×100.)

New diagnostic techniques that facilitate tumor assessment are now available. Spectral domain optical coherence tomography (SD-OCT) aids the detection of subretinal fluid, while fundus autofluorescence (FAF) imaging helps to disclose and confirm the presence of orange pigment. The latter comprises fluorescent lipofuscin pigment within macrophages released from disrupted retinal pigment epithelial (RPE) cells on the surface of an actively growing tumor. More recently, enhanced depth imaging OCT (EDI-OCT) has shown promise in the differential diagnosis of choroidal lesions. EDI-OCT of choroidal nevi typically shows a lesion with a smooth domed surface with chronic RPE changes and photoreceptor atrophy. Nevi lack subretinal fluid and so-called shaggy photoreceptors, which are present in many melanomas.

Uveal nevi are bland spindle cell tumors that comprise the benign end of the biological spectrum of melanocytic neoplasms. Histopathologically, a compact infiltrate of slender pigmented or nonpigmented spindle cells typically replaces the choroidal stroma (Fig. 11-2B). The nevus cells have bland oval or cigar-shaped nuclei that lack nucleoli or nuclear folds and have finely dispersed chromatin. Mitotic activity is absent. In some cases, the nevus cells are plump and dendritic in shape. Intranuclear cytoplasmic inclusions are common in some cases. Foamy balloon cells that appear to be undergoing lipoidal degeneration are found in 4% of nevi. Maximally pigmented, plump, polyhedral nevus cells comprise the magnocellular variant of nevus called melanocytoma (see below).


MELANOCYTOMA (MAGNOCELLULAR NEVUS)

A melanocytoma is a characteristic type of uveal nevus composed of plump polyhedral nevus cells filled with copious quantities of maximally pigmented cytoplasm. Melanocytomas have been called magnocellular nevi. In contrast to most nevi, melanocytoma may be relatively large and may be difficult to distinguish clinically from melanoma (Figs. 11-3 and 11-4).

Melanocytomas classically involve the optic disk but can arise from any part of the uveal tract including the iris, choroid, or ciliary body. Clinically, they are intensely pigmented and often occur in young patients. Unlike melanoma, they do not have a predilection for Caucasians; 37% to 50% of optic disc melanocytomas have been reported in African Americans.

Melanocytomas are so intensely pigmented that they appear black on routine microscopy. The copious cytoplasmic pigmentation typically obscures the nuclei of the melanocytoma cells requiring bleached sections for proper evaluation (Figs. 11-3D and 11-4). When bleached sections are examined, the tumor cells are found to have a low nuclear/cytoplasmic ratio and bland nuclei. Nucleoli usually are inconspicuous, but there are exceptions to the rule. Melanocytomas often undergo spontaneous necrosis and typically contain pigment-laden macrophages. Extensive
tumor necrosis typically is observed more often in a melanocytoma than a melanoma of comparable size, and totally necrotic melanocytomas occasionally are encountered. Melanophages released by partially necrotic iris melanocytomas can cause secondary melanocytomalytic glaucoma by physically obstructing the trabecular meshwork (Fig. 8-16). Transformation into malignant melanoma occurs rarely (1% to 2%).






FIG. 11-3. Melanocytoma. A. Large, intensely pigmented melanocytoma of optic disk in African American woman was enucleated because patient complained of intractable pain and there was concern about malignant transformation. B. Pigmented mass protrudes from the optic disk. C. Intensely pigmented tumor replaces parenchyma of the optic disk. D. Bleached sections revealed no evidence of malignant transformation. (C. H&E ×25, D. Bleach ×25.)






FIG. 11-4. Melanocytoma. A. Copious quantities of melanin pigment obscure nuclear details. B. Bleaching of melanin pigment discloses bland nuclei and low nuclear/cytoplasmic ratio consistent with benign magnocellular nevus. (A. H&E ×250, B. Bleach ×250.)



UVEAL MALIGNANT MELANOMA


Clinical Features

Uveal melanoma is the most common primary malignant intraocular neoplasm in adults in Europe and the United States. On a worldwide basis, retinoblastoma actually is the most common primary intraocular tumor. Kivelä has estimated that there are ˜8,000 cases of retinoblastoma yearly in the world compared to 7,000 cases of melanoma. Uveal melanoma is a tumor with a definite predilection for fair-skinned, blue-eyed Europeans. Approximately two third of uveal melanomas arise in Caucasians of European descent who comprise ˜13% of the world’s population. In contrast, Han Chinese and Bengalis comprise one fourth of the world’s population, yet have only 8% of the uveal melanomas. Uveal melanomas are relatively rare; about 1,800 tumors occur yearly in the United States. The annual age-adjusted incidence in the United States is about 6 cases per 1 million population.

Uveal melanomas arise from the dendritic melanocytes of the uvea, the middle pigmented and vascularized coat of the eye, which includes the iris, ciliary body, and the choroid (Fig. 11-1B). Choroidal melanomas are most common. More than 90% are choroidal tumors. Uveal melanoma affects both sexes equally. Although pediatric and even rare congenital cases have been reported, uveal melanoma generally occurs in older persons. The mean age of patients eligible for treatment in the Collaborative Ocular Melanoma Study (COMS) was 59 years. Less than 0.8% of cases occur in patients less than age 20 years. Older patients tend to have larger tumors and are more likely to die from their tumors after enucleation.

As noted above, race is an important predisposing factor for uveal melanoma. In the United States, the incidence of uveal melanoma in White patients is 8.5 times greater than the incidence in African Americans. The tumor is also relatively uncommon in Latin America and Asia. The incidence of uveal melanoma in the United States is 25 times greater than that in Taiwan, that is, 0.28 per million versus 7 per million.

Caucasian patients who have congenital ocular or oculodermal melanocytosis (nevus of Ota) (Fig. 5-29) are especially at risk to develop uveal malignant melanoma. The tumor is spawned by a diffuse nevus of the uvea, which is evident clinically as hyperchromic heterochromia iridum. Affected patients often have slate-gray epibulbar pigmentation and a bluish discoloration of adnexal skin as well. It has been estimated that about 1 in 400 white patients with oculodermal melanocytosis will develop uveal melanoma in their lifetime. This risk is about 25 times greater than the risk in unaffected patients. Patients with uveal melanoma associated with oculodermal melanocytosis have double the risk for metastasis compared to those without melanocytosis. Melanomas have developed in young patients with Ota nevus. Ocular and oculodermal melanocytosis are relatively common in Asians but do not appear to predispose them to melanoma. Melanoma also can arise in patients who have the combination of ocular melanocytosis and nevus flammeus called phacomatosis pigmentovascularis.

Uveal melanomas occasionally arise from localized uveal nevi, but the estimated incidence of malignant transformation is quite low. Uveal melanoma has been reported in patients with neurofibromatosis type I, the dysplastic nevus or familial atypical mole melanoma syndrome, and the BAP1 cancer syndrome. Uveal melanoma can arise in patients who have a rare paraneoplastic syndrome called benign diffuse uveal melanocytic proliferation or BDUMP syndrome. The tumor’s propensity for blue-eyed individuals and the inferior exposed part of the iris suggests that exposure to ultraviolet light could be a predisposing factor.

The clinical signs and symptoms of uveal malignant melanoma depend largely on the location of the tumor and the extent of the disease when the patient initially seeks medical attention. Most posterior uveal melanomas present with painless visual loss. Visual symptoms are caused most often by serous and/or solid detachment of the retina. Other mechanisms of visual loss include physical obscuration of the fovea by overhanging tumor, cystoid macular edema, cataracts caused by expanding ciliary body tumors, and rarely vitreous hemorrhage, which usually develops when tumors erode through the retina. Melanomas occasionally are found in asymptomatic patients during routine ophthalmologic examinations. Iris melanomas may present as an enlarging pigmented blemish or a change in eye color (heterochromia iridum) (Fig. 8-21). Other tumors present with unilateral glaucoma. Anterior segment melanomas cause secondary glaucoma by directly seeding or infiltrating the aqueous outflow pathways. Posterior segment tumors usually cause secondary closed-angle glaucoma through a pupillary block mechanism or by stimulating iris neovascularization. Infarcted or extensively necrotic tumors can cause prominent inflammatory signs that can mimic orbital cellulitis (Fig. 11-5). Advanced cases with extrascleral tumor extension into the orbit may present with ocular proptosis. Unsuspected melanomas occasionally are found when blind painful glaucomatous eyes with opaque media are examined pathologically. Before the advent of ultrasonography, as many as 10% of blind painful eyes were said to harbor previously undiagnosed tumors. Care should be taken to exclude the presence of an occult tumor preoperatively if ocular evisceration is planned (Fig. 11-6). Distant metastases usually are not evident when the tumor is first detected and treated.



Gross Pathology

Melanomas initially arise in the uveal stroma. In early cases of choroidal melanoma, the profile of the sectioned tumor is oval or almond shaped, and its tissue usually appears relatively cohesive after fixation (Fig. 11-8A). Although some melanomas diffusely infiltrate the uvea, most uveal melanomas are relatively well-circumscribed tumors with distinct margins. In many cases, the growing melanoma perforates the Bruch membrane and enters the subretinal space where
its apical portion typically assumes a spherical shape that often is likened to a mushroom or collar button (Figs. 11-7, 11-8B,D and 11-9). If a choroidal tumor has a mushroom configuration, one can be reasonably certain that it is a uveal melanoma. There are exceptions to this rule, but they are exceedingly rare. Dilated blood vessels typically are found in the mushrooming head of the tumor (Figs. 11-7D and 11-9). The ruptured ends of the Bruch membrane exert a compressive cinch-like effect on the waist of the tumor causing vascular congestion in its apex. Rupture of the Bruch membrane was present in 87.7% of 1,527 large- or medium-sized melanomas examined in the COMS. Retinal invasion was present in nearly half (49.1%), and tumor cells were found in the vitreous body in one fourth. About 3% of melanomas diffusely thicken the choroid without forming an elevated mass. These diffuse melanomas usually are of mixed cell type are more likely to infiltrate the sclera and invade the optic nerve or orbit (Figs. 11-10 and 11-11E). Delayed diagnosis or misdiagnosis is common.






FIG. 11-5. Necrotic melanoma presenting as aseptic orbital cellulitis. A. Swollen and erythematous eyelids and chemotic conjunctiva suggest orbital cellulitis in patient found to have necrotic melanoma. B. MRI disclosed large ciliochoroidal melanoma in mildly proptotic eye. C. Totally necrotic melanoma cells have lost their basophilic DNA. Nuclear profiles serve to identify epithelioid cells. (C. H&E ×400.)






FIG. 11-6. Inadvertently eviscerated choroidal melanoma. A. Large pigmented mushroom-shaped choroidal melanoma is evident in macrophoto of evisceration specimen removed from the blind painful eye of a young Hispanic woman in her mid-20s. B. The tumor contains spindle B, intermediate, and rare epithelioid melanoma cells. The case was referred to an oculoplastic surgeon who did not perform preoperative imaging. He did not suspect a tumor due to the patient’s young age and ethnicity. (B. H&E ×400.)

In the COMS, choroidal melanomas were classified as small, medium, and large based on the tumor’s largest basal diameter (LTD). Small choroidal melanomas measure <10 mm in LTD and appear as a focal discoid or oval area of choroidal thickening. Medium-sized melanomas measure 11 to 15 mm, and large tumors are more than 15 mm in largest basal tumor diameter. Size is an important prognostic feature in uveal melanoma.






FIG. 11-7. Choroidal melanoma. A. Fundus photograph shows mushrooming head of pigmented choroidal tumor elevating inferotemporal retina. B. Tumor seen in wide-angle photograph has broken through the Bruch membrane and assumed characteristic mushroom or collar button configuration. C. Lightly pigmented mushrooming head of choroidal melanoma arises from pigmented base. D. IVFA highlights vascular congestion in tumor apex caused by compressive cinch-like effect of the Bruch membrane on the waist of the tumor.

Choroidal melanomas typically cause an exudative serous detachment of the overlying and adjacent retina. Large tumors may cause total retinal detachment (Figs. 11-8B,D and 11-9). The detached retina typically shows photoreceptor atrophy and microcystoid retinal degeneration. The RPE on the surface of the tumor undergoes atrophy and proliferation forming drusenoid material and occasionally a plaque of metaplastic fibrous tissue. Many tumors infiltrate the overlying retina. The melanoma may perforate the retina in exceptional cases, causing vitreous hemorrhage and tumor seeding of the vitreous and the inner retinal surface. Large tumors may totally fill the globe. Eventually, some melanomas extend extraocularly through the sclera and invade the orbit (Fig. 11-11C,E). Secondary glaucoma is often present in eyes with advanced


or neglected tumors. Uveal melanomas vary markedly in their pigment content. Some tumors are totally amelanotic. Other maximally pigmented tumors appear jet black grossly and must be bleached before they can be interpreted histopathologically. Varying degrees of pigmentation typically are found within a single tumor. The cut surface of some tumors has a marbleized appearance. Clumps of orange pigment are found on the surface of many melanomas (Fig. 11-12). The orange pigment comprises either aggregates of macrophages that have ingested lipofuscin pigment and melanin from the damaged RPE or detached RPE cells termed RPE macrophages (Fig. 11-12C,D). The pigment generally is thought to be a clinical marker for an actively growing tumor and can be highlighted with FAF.






FIG. 11-8. Gross pathology, uveal melanoma. A. Small choroidal tumor has oval or almond configuration. The Bruch membrane is intact. B. Heavily pigmented melanoma has arisen from the equatorial choroid and ruptured through the Bruch membrane. The tumor has a characteristic mushroom or collar button configuration. Infiltration of the retina is seen at the tumor’s apex. Posterior to the tumor, the retina is detached by serous fluid. C. Ciliary body melanoma. Heavily pigmented ciliary body tumor deforms and displaces lens. D. Large choroidal melanoma. Large, heavily pigmented mushroom-shaped melanoma has produced a total retinal detachment and secondary glaucoma.






FIG. 11-9. Mushroom-shaped choroidal melanoma. A. Dilated vessels are present in mushrooming head of choroidal melanoma, which has ruptured through the Bruch membrane. Scleral infiltration is present at the base of the tumor. The adjacent retina is detached and the retina on the tumor’s apex is severely atrophic. B. Arrows point to the edge of rupture in the Bruch membrane. Dilated vessels in mushrooming head of tumor are caused by the compressive cinch-like effect of the ends of the Bruch membrane on the waist of the tumor. The retina is detached by serous fluid. (B. H&E ×5.)






FIG. 11-10. Diffuse ciliochoroidal melanoma. A. Arrows denote thin choroidal infiltrate of melanoma cells on both sides of the globe. B. Parts of uveal melanoma were <200 µm in thickness. C. Spindle cells predominate in this area. Epithelioid cells are found elsewhere. A significant number of lymphocytes infiltrate the tumor. The case initially was diagnosed as uveitis. Diffuse uveal melanoma has a poor prognosis; the patient died several months after enucleation. (B. H&E, ×10, C. H&E ×100.)






FIG. 11-11. Extraocular extension, uveal melanoma. A. Vortex vein invasion by uveal melanoma. The vortex vein in the macrophoto at the left is massively distended by heavily pigmented tumor. B. Photomicrograph shows melanoma in the lumen of the vessel. C. Massive posterior extrascleral extension. Posterior choroidal melanoma has extended extrasclerally forming large pigmented orbital mass that dwarfs the intraocular tumor. Optic nerve invasion is present. The patient presented with ocular proptosis. D. Anterior extraocular extension. Ciliary body melanoma exited globe via anterior emissarial canals. E. Diffuse choroidal melanoma. Melanoma diffusely thickens choroid. Highly aggressive tumor has invaded optic nerve and grown through posterior emissarial canal-forming juxtapapillary epibulbar mass. (B. H&E ×100, E. H&E ×25.)

Ciliary body melanomas are less common than choroidal tumors and tend to have a more spherical shape (Fig. 11-8C). Ciliary body tumors may be larger when they are first detected because they remain hidden behind the iris and often remain asymptomatic because they cause late retinal detachment. Ciliary body melanomas can deform the crystalline lens and cause unilateral cataract. Occasionally, they can invade the anterior chamber and present with iris heterochromia and secondary glaucoma. The glaucoma is caused by seeding of the trabecular meshwork by tumor cells or by circumferential tumor growth around the angle (ring melanoma). Patients with ciliary body involvement have a poorer prognosis.


Histopathology

The biologic spectrum of uveal melanoma cells comprises bland spindle A melanoma cells at one end and wildly anaplastic epithelioid cells at the other (Fig. 11-13). The term spindle cell is derived from the fusiform or spindled configuration of the cells’ cytoplasmic outline. Spindle cells are bipolar in shape, and many have long tapering processes that occasionally are visible when individual pigmented cells are seen in a largely amelanotic tumor. Spindle cells grow in a syncytial fashion and form interweaving fascicles of parallel oriented cells (Fig. 11-14A,B). The cells can be pigmented or nonpigmented.






FIG. 11-12. Orange pigment. A. The presence of orange pigment is one of the factors that predicts that a pigmented choroidal lesion will grow and probably is a melanoma. B. Clumps of orange pigment adhere to posterior surface of detached retina overlying actively growing melanoma. C. Orange pigment is composed of aggregates of macrophages that have phagocytized lipofuscin and melanin pigment released by RPE cells that have been disrupted by an actively growing tumor. D. Macrophages that have ingested lipofuscin pigment are PAS positive. (C. H&E ×250, D. PAS ×100.)

There are two types of spindle cells, spindle A and spindle B, which are distinguished by their nuclear characteristics. Spindle A nuclei are cigar-shaped and have finely
dispersed chromatin (Fig. 11-14A). Many spindle A cells have a longitudinally oriented chromatin stripe caused by a fold in the nuclear membrane. If a nucleolus is present, it usually is inconspicuous. The nuclei of spindle B cells tend to be plumper and more oval in shape and have coarser chromatin and distinct nucleoli (Fig. 11-14B).

Epithelioid melanoma cells comprise the poorly differentiated end of the cytologic spectrum. Uveal melanomas that contain epithelioid cells have a poorer prognosis. The term epithelioid, which means “epithelial-like,” reflects the superficial resemblance of the tumor cells to simple epithelial cells. Epithelioid cells have abundant cytoplasm and are often polygonal in shape (Fig. 11-14C). They have distinct cytoplasmic margins, are poorly cohesive, and do not grow as a syncytium. The nuclei of epithelioid cells typically are round or oval in shape, and they often appear vesicular due to margination or clumping of chromatin along the inner side of the nuclear membrane. Epithelioid melanoma cells also have prominent nucleoli that are often large and reddish-purple in color. The large nucleoli are often visible at lower magnification. Variants of epithelioid cells include wildly anaplastic tumor giant cells (Figs. 11-13G-I and 11-15) and relatively uniform small epithelioid cells (Fig. 11-16A).

During histopathologic assessment, melanoma cells are classified by their nuclear characteristics. Spindleshaped cells that have epithelioid nuclei occasionally are encountered; such cells are classified as epithelioid. In recent years, the term intermediate cell has been used more and more. Intermediate cells have nuclear characteristics that are intermediate between spindle B and epithelioid. For example, one might apply the term intermediate cell to a spindle B cell that has a nucleus that is somewhat large and has a fairly prominent nucleolus.

Occasionally, spindle cells in a uveal melanoma are arranged radially around vessels or perpendicular to

fibrovascular septa (vasocentric pattern), or their nuclei form rows that resemble the Verocay bodies or the Antoni A pattern seen in schwannoma (Verocay pattern). Melanomas are called fascicular if these patterns dominate (Fig. 11-16B). Fascicular melanoma was a separate category in the Callender initial classification that was dropped from McLean’s 1983 modification.






FIG. 11-13. The biological spectrum of uveal melanoma. Melanocytic lesions of the uveal tract comprise a biologic spectrum; tumor cells become progressively less differentiated as mutations accumulate. The benign end of the spectrum includes spindle nevus cells (A), low-grade spindle melanoma cells (B), and spindle B cells (C). Intermediate cells (D) are spindle shaped but have nuclear characteristics intermediate between spindle B and epithelioid. The malignant end of the spectrum comprises epithelioid cells (E-I) that have distinct cytoplasmic margins and prominent nucleoli. They include wildly anaplastic tumor giant cells (G-I). (All figures, H&E, original magnification ×400.)






FIG. 11-14. Uveal melanoma cells. A. Spindle A melanoma cells. Many of the cells in the photo have spindle A nuclear characteristics. The nuclei are bland, slender, and cigar shaped and have finely dispersed chromatin and indistinct nucleoli. Longitudinal folds in the nuclear membrane are apparent microscopically as a chromatin stripe or line. The spindle cells form a syncytium with indistinct cytoplasmic borders. B. Spindle B melanoma cells. Most of the cells in this field are spindle B melanoma cells. They have oval nuclei and an obvious nucleolus. Compared to spindle A cells, their chromatin is more coarsely clumped. The spindle cells form a syncytium. C. Epithelioid melanoma cells. The cytoplasmic margins of these large, poorly cohesive epithelioid melanoma cells are easily discernible. Epithelioid cell nuclei are typically round and have peripheral margination of coarsely clumped chromatin. Epithelioid cells usually have prominent reddish-purple nucleoli. They typically are polyhedral in shape and have copious amounts of cytoplasm. D. Uveal melanoma, mixed cell type. Mixed cell melanomas are composed of a mixture of spindle (above) and epithelioid cells (below). (All figures H&E ×250.)






FIG. 11-15. Tumor giant cells, uveal melanoma. Tumor giant cells are highly anaplastic epithelioid cells. They are relatively rare, and their prognostic significance is uncertain. (A. H&E ×50, B. H&E ×100.)

Varying degrees of necrosis may be found (Fig. 11-5C). Necrosis tends to be more prominent in rapidly growing high-grade tumors, or tumors that have had prior brachytherapy, and may produce inflammatory signs clinically. The necrosis may be patchy and focal, or may involve extensive parts, or even all of the tumor. Aggregates of melanophages typically are found in the necrotic areas. Total infarction of the tumor (and other intraocular structures) may occur in eyes with severe secondary closed-angle glaucoma. As mentioned above, melanocytoma is especially prone to spontaneous necrosis. The latter diagnosis should always be considered when a totally necrotic, heavily pigmented tumor is found.

Choroidal melanomas produce abnormalities in the overlying RPE including atrophy, hyperplasia, and the formation of drusen and drusenoid material. The overlying retina often shows photoreceptor loss and may develop cystoid edema. The latter tends to be more common over slower growing lesions, especially choroidal hemangiomas. After the Bruch membrane has ruptured, the vessels located in the mushrooming head of the tumor are often quite prominent, reflecting vascular stagnation caused by the compression at the waist of the tumor (Fig. 11-9). Aggregates of macrophages that have ingested PAS-positive lipofuscin pigment and melanin from the damaged RPE or perhaps detached RPE cells can be found in the subretinal fluid (Fig. 11-12). These are evident ophthalmoscopically as clumps of orange pigment that serve as a clinical marker for an actively growing neoplasm.

Uveal melanomas are placed into four categories based on their cytology. Tumors composed entirely of spindle A cells or even blander nevus cells are classified as spindle cell nevi. Tumors composed of a mixture of malignant spindle A and spindle B cells are called spindle melanomas. Melanomas of mixed cell type contain a mixture of spindle and epithelioid melanoma cells (Fig. 11-14D). Some laboratories specify the predominant cell type found in a mixed cell melanoma, for example, reporting mixed cell, predominantly spindle if only a few epithelioid cells are present. Epithelioid melanomas are composed predominantly of epithelioid cells. They are relatively rare and have the poorest prognosis. Most medium- and large-sized melanomas contain a mixture of spindle and epithelioid cells. Eighty-six percent of the posterior melanomas in the COMS histopathology study were classified as mixed cell type; 8% were of spindle cell type and 5% were epithelioid. The association between cytology and mortality is known as the Callender classification (see section on “Prognostic Factors” below).


Prognostic Factors

About one half of patients with choroidal and ciliochoroidal malignant melanomas eventually die from their tumors. Because the eye and orbit lack lymphatics, uveal melanoma spreads via the bloodstream. Hematogenous metastasis to the liver occurs most often; more than 90% of cases with metastatic melanoma have liver metastases, and they are the first metastases detected in 80% (Fig. 11-17B). For this reason, liver enzymes and hepatic imaging are used clinically to monitor patients for recurrence. Other common sites of metastatic uveal melanoma include the lung (24%) and bone (16%). Multiple sites are found in 87%. Micrometastases in the liver are not evident clinically and may remain dormant for many years.






FIG. 11-16. A. Small epithelioid cells. Although these cells are relatively small, they definitely are epithelioid in character. They are polyhedral in shape and have distinct cytoplasmic outlines and round or oval nuclei with prominent nucleoli. Clones of small epithelioid cells are encountered occasionally in uveal melanoma. B. Fascicular melanoma. The fascicular category of uveal melanoma was deleted from the revised Callender classification because cellular arrangement does not appear to affect prognosis. This amelanotic melanoma has a striking fascicular appearance. The nuclei of its constituent spindle cells form rows that resemble the Antoni A pattern of Schwannoma. (A. H&E ×400, B. H&E ×50.)


Grossniklaus examined biopsies of liver tissue from patients dying from metastatic uveal melanoma and found that they contained three stages of metastases. Stage I metastases, which were most common, comprised small clusters of tumor cells measuring <50 µm in diameter that were present in the sinusoids of the liver. Based on size, stage II and III metastases were defined as 51 to 500 µm and >500 µm, respectively. The architecture of stage II metastases mimicked the surrounded hepatic parenchyma, while stage III metastases showed either a lobular or portal growth pattern. The mean vascular density and mitotic index of the metastases increased with increasing size. Stage I metastases were not vascularized and showed little mitotic activity, consistent with small, apparently dormant micrometastases.

It is now generally believed that metastasis already has occurred in many cases before the melanoma is diagnosed and treated. Unfortunately, once distant metastases are manifest clinically, therapy generally is ineffective. More than 50% of patients who have metastatic uveal melanoma die within 1 year. In recent years, there has been an effort to identify prognostic factors that could identify patients at high risk for metastatic disease who hopefully might benefit from prophylactic chemo- or immunotherapy (Fig. 11-18). These include factors evident on routine clinical examination, factors disclosed by routine histopathologic evaluation, and powerful new factors that require special testing. Prognostic factors evident on clinical examination include the size of the tumor and the presence or absence of ciliary body involvement and extraocular extension. These three clinical factors are used to prognostically stratify uveal melanomas in the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Tumor size is particularly important. In the seventh edition of the AJCC Cancer Staging Manual, melanomas are divided into four size categories based on their largest basal diameter and thickness in millimeters. Tumors >18 mm in diameter are class 4. Tumors that involve the ciliary body have a poor prognosis, as do tumors that have extended out of the eye.

Other aspects of tumor size that typically are measured and recorded by ophthalmic pathologists include the size of the melanoma’s transillumination shadow and the dimensions of the tumor on the cut surface of the globe. Both are measured during gross dissection of the eye. In addition, the tumor’s largest basal diameter and height are measured on the glass slide at the time of microscopic evaluation.

In addition to tumor size, ciliary body involvement, and extraocular extension, prognostic factors evident on routine histopathologic examination include the cytologic characteristics of the tumor cells (cell type or Callender classification) discussed above, mitotic activity, and the presence of vascular mimicry patterns (i.e., vascular loops and networks) and tumor-infiltrating lymphocytes and macrophages.

Cell type or the Callender classification refers to the relationship between mortality and the characteristic of the melanoma’s cells. This association initially was reported in 1931 by Major George Russel Callender who examined a series of cases on file in the Registry of Ophthalmic Pathology at the Army Medical Museum in Washington, DC. Callender observed that melanomas were composed of two types of spindle cells that he designated spindle A and B and less differentiated epithelioid cells. He found that tumors that contained epithelioid cells had a poorer prognosis. Ian McLean and his coworkers at the Armed Forces Institute of Pathology modified the Callender original classification in 1978.

In actuality, uveal melanoma represents a biological spectrum (Fig. 11-13). The appearance of morphology of the melanoma cells evolves as mutations accumulate, and the cells become progressively less differentiated. The Callender classification is an attempt to pigeonhole this biologic spectrum.






FIG. 11-17. A. Dr. Lorenz E. Zimmerman conducting ophthalmic pathology conference at the Armed Forces Institute of Pathology in Washington, DC circa 1978. A short time later, “Zimm” formulated his hypothesis concerning the effect of enucleation on the dissemination of uveal melanoma. B. Liver metastases, uveal melanoma. Postmortem examination of patient who died from metastatic uveal melanoma shows massive replacement of liver by tumor. (A. Photo by the author, B. Slide courtesy of Dr. Daniel M. Albert.)


The presence or absence of epithelioid cells is an extremely important prognostic factor in uveal melanoma. McLean reviewed a series of 3,432 cases of malignant melanoma of the choroid and ciliary body on file in the AFIP’s Registry of Ophthalmic Pathology and found that 56% were mixed cell tumors composed of a mixture of spindle and epithelioid cells. The 15-year mortality of patients with melanomas of mixed cell type was three times that of patients whose tumors were composed solely of spindle cells. Tumor size, measured as the largest tumor diameter (LTD), was also highly correlated with mortality.

The modified Callender classification remains an important and reliable prognosticator of mortality from uveal melanoma. Tumor mortality is greater if uveal melanomas contain epithelioid cells (epithelioid melanomas or mixed epithelioid/spindle cell type). The 5-year mortality of uveal melanomas that contain epithelioid cells is 42%. At 15 years, death from metastatic melanoma increases to 63%. The prognosis of spindle cell tumors is much better; 90% survive 5 years and 72% survive 15 years. Although rare fatal spindle A melanomas have been reported, most tumors composed entirely of spindle A cells are thought to be benign spindle cell nevi.

Cell type remains one of prognostic mainstays of surgical pathologists because assessment is relatively rapid and requires no special stains or equipment. However, determination of cell type is highly subjective, and diagnostic accuracy can vary with the expertise and experience of the pathologist. A masked study showed that even experienced ophthalmic pathologists disagree about their classification of individual tumor cells. Secondly, uveal melanoma’s biological spectrum, which includes extremely bland spindle A melanoma cells at one end and highly anaplastic epithelioid cells at the other, includes only three diagnostic categories, spindle, mixed, or epithelioid, and tumors in a single category, for example, mixed cell type, can vary significantly in their apparent degree of differentiation.






FIG. 11-18. Prognostic features in uveal melanoma. Prognostic features evident on clinical examination include large tumor size (A) and the presence of ciliary body involvement (B) and extraocular extension (C). These are the major factors included in the AJCC tumor classification. In addition to the above, prognostic factors evident on routine histopathologic examination include a cell type with epithelioid cells (D), mitotic activity (E), the presence of vascular mimicry patterns (F), tumor-infiltrating lymphocytes (G) and tumor-infiltrating macrophages (H). Powerful factors that require special testing include assessment for nonrandom chromosomal abnormalities such as monosomy 3 (I) and the tumor’s gene expression profile. Melanomas with class 2 GEP have a significantly poorer prognosis. (D. H&E ×400, E. H&E ×400, F. PAS ×50, G. H&E ×400, H. H&E ×250, I. FISH). (Figure J courtesy of J. William Harbour MD.)


The limitations of the Callender classification prompted a search for more objective and reliable criteria for the histopathological assessment of the malignant potential of uveal melanomas. Gamel and coworkers showed that certain nucleolar parameters, most notably the inverse of the standard deviation of the area of the nucleolus and a second simpler objective method of nucleolar assessment based on the measurement of the 10 largest nucleoli (MTLN), were useful predictors of death from metastatic melanoma. Although these techniques more accurately predicted survival after enucleation using morphological data contained within routine histologic slides, they were not widely adopted because they were labor intensive and relatively time consuming and required special expertise and equipment.

Other attempts to make the assessment of cell type more objective and quantitative include counting the number of epithelioid cells and intermediate cells in 40 high-power fields (HPFs). (The mitotic activity of uveal melanoma is routinely assessed by counting the number of mitotic figures in 40 HPFs.)

As noted above, tumor size is an important prognostic factor. Large melanomas have a poorer prognosis than medium- and small-sized melanomas. Tumor size generally is recorded as the largest tumor diameter or LTD measured at the base. The 5-year survival of small (<10 mm), medium (10 to 15 mm), and large (>15 mm) melanomas are 86%, 66%, and 56%, respectively. These survival rates drop to 76%, 51%, and 41% at 10 years and 70%, 43%, and 35% at 15 years. Smaller melanomas are more likely to be spindle cell tumors. Furthermore, they are more likely to have disomy of chromosome 3 and a more favorable class I gene expression profile.

Certain extracellular matrix patterns within uveal melanomas that initially were termed microvascular patterns have been shown to be prognostic indicators for death from metastatic melanoma. The so-called vascular loops and networks composed of back-to-back loops encircling microdomains of tumor are the vascular mimicry patterns that are strongly associated with death from metastatic melanoma (Fig. 11-18F). The term vasculogenic mimicry looping matrix patterns has been applied to these patterns in recent publications.

Other prognostic factors, which have been shown by multivariant statistical analysis to be less important, include mitotic activity, extraocular tumor extension, necrosis, pigmentation, anterior location, and lymphocytic infiltration. Paradoxically, the prognosis of heavily pigmented tumors may be slightly poorer.

Ocular pathologists routinely assess the mitotic activity of uveal melanoma by counting the number of mitotic figures in 40 high-power (“high dry”) microscopic fields. Forty fields are counted because most uveal melanomas contain relatively few mitoses, that is, only 5 or 10 per 40 HPF. Not unexpectedly, patients whose tumors have more mitoses have a poorer prognosis.

About 8% of 1,527 enucleated globes with uveal melanoma evaluated in the COMS had some degree of extrascleral extension on histopathologic examination (Figs. 11-11 and 11-18C). Although direct scleral infiltration occurs in some cases, melanomas typically extend out of the eye through the emissarial canals of vessels and nerves in the sclera or via the lumina of the vortex veins (Fig. 11-11A,B). Unlike retinoblastoma, uveal melanoma rarely invades the optic nerve. Coupland and Damato found that extraocular spread correlates with increased mortality because it is associated with increased tumor malignancy and, in the case of posterior tumors, more advanced disease.

The presence of tumor-infiltrating lymphocytes is associated with decreased survival (Fig. 11-18G). De la Cruz et al. examined 1,078 cases of uveal melanoma with known survival and found that 12.4% harbored 100 or more lymphocytes per 20 high-power (×400) microscopic fields. The survival rate at 15 years was 36.7% for patients in the high lymphocytic group and 69.6% for patients in the low lymphocytic group. This seemingly counterintuitive observation is explained by the fact that extraocular dissemination of tumor cells is a requisite for stimulation of a T-lymphocyte-mediated immune response. The latter reflects the eye’s status as an immunologically privileged site.

The number of tumor-infiltrating CD68-positive macrophages infiltrating the tumor is another prognostic factor (Fig. 11-18H). Tumor infiltration by M2-type macrophages, the main type found in uveal melanoma, is associated with decreased survival. Tumors with monosomy of chromosome 3 contain a greater number of M2 macrophages than tumors with disomy of chromosome 3. M2-type macrophages are alternatively activated macrophages that promote angiogenesis and have anti-inflammatory properties.

The most powerful prognostic indicators of uveal melanoma require special testing. These include the presence of certain nonrandom chromosomal abnormalities in the tumor cells and the tumor’s gene expression profile (Fig. 11-18I). Uveal melanomas harbor recurrent nonrandom chromosomal abnormalities that include monosomy 3, trisomy 8, and structural or numerical abnormalities of chromosome 6. Loss of chromosome 3 and gains in chromosome 8 are associated with metastatic death. Monosomy 3 has been shown to be a significant predictor of poor prognosis in uveal melanoma. In one study, 57% of patients with monosomy 3 had developed metastases at 3 years, compared to none of the patients with disomy 3. Chromosomal 3 abnormalities have been identified using a variety of techniques including fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification and DNA amplification, and microsatellite assay.

Harbour and coworkers initially examined the expression of genes in uveal melanomas using microarray
technology and found that they fell into two classes that differed markedly in survival (Fig. 11-18J). Their gene expression profile of class I tumors resembles melanocytes. They are low grade and have less than a 5% incidence of metastasis. In contrast, the risk for metastasis in patients who have class II melanomas is >90%. The gene expression profile of class II melanomas resembles primitive neural or ectodermal stem cells. These tumors typically contain epithelioid cells and have monosomy of chromosome 3 and vascular mimicry patterns. They are characterized by downregulation of neural crest and melanocyte-specific genes and upregulation of epithelial genes. Recently, a subclass of class I termed class IB has been recognized. Affected patients develop late metastases. Tumors with gene expression profile 1B harbor mutations in the preferentially expressed antigen in melanoma (PRAME) gene. Gene expression profiling (GEP) of uveal melanomas currently is available as a proprietary test that assesses tumor class by examining 13 genes. The test’s proponents believe that it is the most accurate prognostic marker for melanoma mortality and metastasis, but this remains controversial.

Many centers are now submitting specimens for GEP testing. Others rely on monosomy 3, which can be assessed using several methods. The use of these powerful ancillary tests is somewhat controversial because there currently is no effective treatment for metastatic uveal melanoma. Patients at risk for metastatic disease can be identified, but clinicians currently have no effective treatment to offer them. Many patients want to know their prognosis, however, and those in the low-risk categories can be reassured and followed less rigorously. In addition, GEP can exclude patients at low risk for metastasis from clinical trials investigating new therapeutic agents. Inclusion of class I patients would bias the results of such studies.


The Genetics of Uveal Melanoma

The mitogen-activated protein kinase pathway (MAP-K) is activated in 86% of uveal melanomas. In most melanocytic lesions, the oncogenic mutations in the MAP-K signaling pathway are located in BRAF and NRAS1. BRAF stands for (v-raf murine sarcoma viral oncogene homolog B1). Sixty-four percent of cutaneous melanomas have activating mutations in BRAF and 90% of these are the V600E mutation in which there is replacement of the normal valine at position 600 in the molecule by glutamic acid. The 600 E mutation is the target for the BRAF enzyme inhibitor vemurafenib, which successfully controls melanoma that harbor this mutation, albeit for a short period time. Unfortunately, BRAF mutations are rare in uveal melanoma, but they do occur in conjunctival melanoma.

Mutations in GNAQ/GNA11 are an alternate route to MAP kinase activation in uveal melanoma. GNAQ stands for guanine nucleotide-binding protein G(q) subunit alpha. This gene encodes a guanine nucleotide-binding protein that couples the seven transmembrane domain receptor to activation of phospholipase C-beta. GNAQ/GNA11 mutations have been found in 83% of blue nevi and 46% of uveal melanomas. They appear to be an early event since they are also present in blue nevi and the nevus of Ota. GNAQ/GNA11 mutations also activate YAP in the Hippo pathway, which may be inhibited by verteporfin.

Inactivating mutations in the BAP1 gene play an important role in the metastasis of uveal melanoma. BAP1 stands for breast cancer 1, early onset (BRCA1)—associated protein-1 gene. BAP1 mutations are found in 84% of class II melanomas. The BAP1 gene is located on chromosome 3, and the inactivating mutations are thought to be disclosed by loss of chromosome 3 in tumors with monosomy 3. An autosomal dominantly inherited familial cancer syndrome is caused by mutations in BAP1. Patients with the BAP1 cancer syndrome develop uveal melanomas, mesotheliomas, and benign atypical melanocytic skin tumors. These BAP1-mutated atypical intradermal tumor (MBAITS) are biphasic nevus-like lesions. They contain a conventional junctional, compound, or intradermal component composed of small BAP1-positive melanocytes and an adjacent dermal lesion composed of BAP1-negative epithelioid melanocytes.


Iris Nevus and Melanoma

Most melanocytic lesions of the iris are benign nevi or low-grade spindle cell tumors (Figs. 11-19, 11-20, 11-21, 11-22). About half of the adult population has small nonprogressive iris nevi called freckles (Fig. 11-19). Larger pigmented iris lesions initially should be observed for growth. In one series, only 6.5% enlarged during a 5-year observation period. Clinical features that suggest that a pigmented iris tumor is a melanoma include large size, documented growth, elevated intraocular pressure, hyphema, and tumor vascularity. Other risk factors for malignant transformation include a diffuse gross pattern and ectropion iridis. Subsequently, Shields and coworkers analyzed 1,611 patients with iris nevus to determine factors predictive of growth into melanoma. In that series, 8% had transformed into melanoma in 15 years. That paper included an ABCDEF mnemonic that listed risk factors for malignant transformation. They included: A = age, young (<40 years), B = blood in the anterior chamber (hyphema), C = clock hour (mass located inferiorly), D = diffuse configuration and F = feathery margins. Diffuse growth pattern and hyphema were the most powerful risk factors.

The mean age of patients with iris melanomas is about 10 years younger (age 43 years) than the age of patients with posterior segment melanomas. The prognosis of iris melanoma is also relatively favorable compared to tumors of the posterior segment. Shields studied 169 patients with histologically confirmed iris melanoma and found that distant metastases developed in 5% at 10-year follow-up. In that series, metastases were more likely to develop in older patients whose tumors involved the angle or iris

root and had elevated intraocular pressure and extraocular extension. The relatively small size of most iris melanomas probably is a major factor in their good prognosis. The majority are low-grade spindle cell melanomas as well. Iris melanomas that contain epithelioid cells occasionally are encountered however (Figs. 11-20B and 11-21).






FIG. 11-19. Iris freckle. A. Sharply delimited colony of nevus cells in SEM is located anterior to the plane of the surrounding iris stroma. Round cellular processes decorate surface of nevus. B. Iris freckles are small nonprogressive nevi that occur in nearly half the adult population. Their constituent cells have rounded cellular processes that are densely packed with large melanosomes. (A. False-colorized SEM ×160 [modified from Eagle RC Jr. Congenital, developmental and degenerative disorders of the iris and ciliary body. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Clinical Practice, vol. 1. Philadelphia, PA: Saunders, 1993:367-389], B. Epon section, PD ×100.)






FIG. 11-20. Iris melanoma. A. Spindle cells with long tapering processes are cover surface of iris melanoma. B. Low-grade spindle cell melanoma of the iris. Moderately pigmented spindle cells infiltrate and thicken stroma and form plaque on anterior iridic surface. The nuclei of the tumor cells are quite bland. C. Mixed cell melanoma of the iris. SEM discloses bizarrely pleomorphic cells presumed to be epithelioid cells on surface of tumor. D. Mixed cell melanoma of the iris. The heavily pigmented tumor is composed of a mixture of spindle and epithelioid melanoma cells. The epithelioid cells in the stroma are distinguished by their round cytoplasmic profiles and round nuclei with prominent nucleoli. The tumor cells form a plaque on the anterior surface of the iris. (A. SEM ×640, B. H&E ×50, C. SEM ×320 [Modified from Eagle RC Jr. Iris pigmentation and pigmented lesion: an ultrastructural study. Trans Am Ophthalmol Soc 1989;87:581-687], D. H&E ×50.)

Diffuse iris melanomas that cause hyperchromic heterochromia iridis and secondary glaucoma are a rare but clinically important group of iris tumors (Fig. 8-21). Many diffuse iris melanomas are higher-grade tumors that contain epithelioid cells, which are poorly cohesive and prone to aqueous dispersal. Patients are often misdiagnosed clinically and undergo filtering surgery for glaucoma. The latter invariably fails and puts patients at greater risk for extraocular extension and metastasis. Multicentric tapioca melanoma is a variant of diffuse iris melanoma whose cells form nodular aggregates on the anterior surface of the iris reminiscent of the appearance of the pearl form of tapioca used to make tapioca pudding (Fig. 11-22). Pigmented tumors of the iris pigment epithelium are exceedingly rare (Fig. 11-23).

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Oct 28, 2018 | Posted by in GENERAL | Comments Off on Intraocular Tumors in Adults
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