Eye and Orbit

Clinical Features

† Deceased

• Usually pigmented (may be amelanotic), nodular, elevated lesion with vascularity, anywhere on conjunctiva

• Usually mobile, but may be fixed to sclera

• Indistinct edges

• More common in fair-skinned patients

• Frequently develops from malignant patches of primary acquired melanosis

• Metastasize to regional lymph nodes, as well as lungs, liver, brain, bone, and skin through lymphatics

• Incidence increasing in the United States

Gross Pathology

• Noncontributory

Histopathology

• Mixtures of cell types, including small polyhedral cells, spindle cells, epithelioid cells, and balloon cells ( Figure 20.1 )

  

• Normal polarity is lost

• Invasion of overlying epithelium by tumor cells

• May have epithelial cysts if arising from nevus

• In more aggressive lesions, mitotic figures may be present

• Often inflammation is found at the base of the lesion

Special Stains and Immunohistochemistry

• S-100 protein (low specificity, high sensitivity)

• HMB-45 and HMB-50 combination is less sensitive but more specific for melanomas; can be used to distinguish between benign and malignant lesions

• Melan-A (MART-1) staining can be used to determine the extent of the lesion

• Bcl-2 (antiapoptotic cell death protein) is a more robust and consistent marker

• MIB-1 (Ki-67) used to assess proliferative index and is a marker for aggressive behavior

• Tumor-suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN), and the heat-shock protein HSP-90 can also aid in differentiating conjunctival nevus from melanoma

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Most common primary malignant intraocular tumor

• Incidence of 5 to 7 per 1 million general population per year

• Incidence of 20 per million per year in Caucasians older than 50 years

• Unlike cutaneous melanomas, incidence rates do not vary by latitude

• Lifetime risk of 1 in 2500 for whites

• Median age at presentation is in the sixth decade

• Less than 1% occur in patients younger than 18 years

• Slightly more prevalent in men and patients with light complexions, blond hair, and blue eyes

• No known hereditary component, although a few familial occurrences have been reported

• Pregnancy is suggested to enhance growth of melanoma and metastases

• With oculodermal melanocytosis (nevus of Ota) in a white person, there is a lifetime risk of 1 in 400

• About 50% harbor mutations in GNAQ gene, which is also seen in precursor lesions

• BAP1, GNA11, EIF1AX, and SF3B1 germline mutations are other driver-mutated genes associated with increased risk

• Patient may be asymptomatic or may complain of blurred vision because of direct tumor involvement of macula, detachment of retina from subretinal fluid produced by tumor, vitreous hemorrhage, or massive size of tumor obscuring vision

• Variably pigmented, elevated, initially flat or dome-shaped lesion noted in fundus, sometimes with orange pigment on its surface

• Slow growing

• Anterior (ciliary body) position may be associated with segmental cataract

• Anterior (ciliary body) tumors

  • More difficult to visualize

  • Can attain a large size before clinically recognized

  • Associated with ≥1 dilated episcleral blood vessels, epibulbar pigmented lesion, cataractous lens, and secondary glaucoma

  • Can be dome shaped or have a diffuse circumferential growth pattern (ring melanoma)

  • High-frequency ultrasound biomicroscopy allows for better imaging of the ciliary body

• Choroidal melanomas can be flat and diffuse, making clinical diagnosis more difficult

• Ultrasonography demonstrates solid tumor with low to medium internal reflectivity

• CT and MRI are used to evaluate extrascleral extension and differentiate intraocular hemorrhage and atypical vascular lesions from melanoma

Gross Pathology

• Mushroom-shaped or dome-shaped pigmented mass in choroid or ciliary body

• When these tumors arise in the choroid (as opposed to the ciliary body), they may rupture through the overlying Bruch membrane and extend into the subretinal space (giving a mushroom or collar-button shape)

• Size and location are important prognostic factors (size greater than 1 cm ³ and location at the ciliary body or over the optic nerve are poor prognosticators)

• Extrascleral extension can be seen, usually through scleral canals with vortex veins; this too is an important poor prognosticator

• Occasionally may extend into the subconjunctival space and be mistaken for a primary conjunctival lesion

Histopathology

See Figure 20.6 .

• Most tumors probably arise from preexisting nevi in the choroid (not retinal pigment epithelium); others arise de novo

• Cell types (Callender histologic classification is most commonly used)

  • Spindle A

    • About 5% of melanomas (second least common)

    • Highly cohesive cells with spindle-shaped nuclei having a central stripe of chromatin (caused by nuclear fold)

    • Spindle cells grow as a syncytium, making cell boundaries difficult to identify

    • Rare mitoses

    • High survival rate (>90%)

    • Pure spindle A tumors are now considered benign and incapable of metastasis

  • Spindle B

    • Nuclei are larger and plumper than spindle A nuclei and contain prominent nucleoli rather than nuclear folds

    • Common type (about 35% to 40% of all melanomas)

    • Indistinct cell boundaries

    • Mitotic figures are rare, although more common than in spindle A

    • Often arranged in fascicular (herringbone) pattern

    • Moderate survival rate (about 75%)

  • Epithelioid

    • Rarest type (about 3%)

    • Noncohesive large cells with large nuclei and abundant cytoplasm

    • High degree of pleomorphism

    • Mitoses more common

    • Poor prognosis; survival of about 28%

  • Mixed

    • Most common type (about 45%)

    • By definition contains a mixture of epithelioid and spindle cell types

    • Usually spindles predominate, but the presence of epithelioid cells classifies the tumor as mixed and portends a worse prognosis

    • Survival rate about 40%

  • Necrotic

    • Rare

    • Tumor is so necrotic as to be unidentifiable in cell type

    • Survival approximates that of mixed-cell type

    • Most tumors have some necrosis

    • Balloon cells commonly found and may represent aging apoptotic cells

    • Inflammatory infiltrates commonly seen within tumor, composed mostly of T-cell lymphocytes

    • Macrophages (melanophages) are commonly seen scattered throughout melanomas

    • Degree of pigmentation varies between tumors and even within an individual tumor (varies from amelanotic to deeply pigmented)

• The most recent TNM classification system for uveal melanomas is published in the 8th Edition AJCC Cancer Staging Manual and is based on the size of the primary tumor and the extent of systemic metastases

Special Stains and Immunohistochemistry

• Frequently HMB-45 positive (about 50%), more specific

• Commonly S-100 positive (>90%), very sensitive

• Melan-A, tyrosinase, and microphthalmia transcription factor (MITF) are additional melanocytic markers

Other Techniques for Diagnosis

• Gene expression profile (GEP) using a 12-gene expression classifier identified two classes of tumors:

  • Class 1 melanoma resembles melanocytes, and <5% of these metastasize

  • Class 1 is further divided into Class 1A (2% 5-year metastatic risk) and Class 1B (21% 5-year metastatic risk)

  • Class 2 melanoma resembles primitive neural or ectodermal stem cells, and 90% of these metastasize (72% 5-year metastatic risk)

Differential Diagnosis