- 1.
What is the most common malignant intraocular neoplasm?
Uveal metastasis, usually from a distant primary carcinoma, is thought to be the most common malignant intraocular neoplasm. An estimated 66,000 patients develop uveal metastases each year. However, most are terminally ill patients, few of whom are evaluated ophthalmologically or pathologically. In contrast, only 1800 cases of uveal melanoma and 300 cases of retinoblastoma occur yearly in the United States.
Many textbooks state that uveal malignant melanoma is the most common primary intraocular tumor, but this statement actually applies only to the United States and Europe, because uveal melanoma has a propensity for fair-skinned, blue-eyed persons. Throughout Africa, Asia, and South America, where melanoma is relatively rare, retinoblastoma is the most common primary intraocular tumor. Kivelä has estimated that approximately 1000 more retinoblastomas than uveal melanomas occur yearly in the world.
- 2.
What is the characteristic shape of choroidal malignant melanoma?
Approximately 60% of choroidal malignant melanomas have a mushroom or collar-button configuration ( Fig. 51-1 ). Melanomas initially have a dome or almond shape when they arise in the choroid. The mushroom or collar-button configuration develops after the tumor ruptures or erodes through the Bruch’s membrane and invades the subretinal space, where it forms a round or ovoid nodule.
Figure 51-1
Mushroom-shaped choroidal melanoma.
- 3.
Is a mushroom configuration pathognomonic for choroidal melanoma?
A mushroom or collar-button configuration almost always signifies that a choroidal tumor is a malignant melanoma. Few things in medicine are pathognomonic, however. Exceedingly rare mushroom-shaped choroidal metastases, hemangiomas, and schwannomas have been reported.
- 4.
What important prognostic features of uveal melanoma can be assessed during routine histopathologic examination?
Tumor size and cell type are two of the most important prognostic factors that can be assessed during routine histopathologic evaluation of uveal melanoma. Larger tumors and tumors that contain epithelioid cells have a poorer prognosis. Tumor size generally is expressed in millimeters as the largest basal tumor diameter. Other prognostic features include mitotic activity (expressed as the number of mitoses in 40 high-power fields), the presence of extrascleral extension, extracellular matrix patterns called vascular loops and networks, lymphocytic infiltration, and involvement of the ciliary body.
- 5.
What factors does the American Joint Commission on Cancer (AJCC) Cancer Staging Manual use to stage uveal melanoma?
Tumor size, ciliary body involvement, and extraocular extension are important factors used to prognostically stratify uveal melanomas in the AJCC’s TNM classification (T is the size of the tumor, N denotes lymph node involvement, M is for metastasis). The staging manual includes a chart that uses both the tumor’s largest basal diameter and its largest thickness to assign tumors to size categories. Tumors greater that 18 mm in diameter are in size category 4. Tumors that involve the ciliary body and/or show extraocular extension have a poorer prognosis.
- 6.
What is the Callender classification?
In 1931, Major George Russell Callender reported that there was an association between survival and histologic characteristics of uveal melanomas called cell type . Callender showed that uveal melanomas may contain two types of spindle cells (spindle A and spindle B cells) and less-differentiated epithelioid cells. Dr. Ian McLean modified Callender’s classification in 1978. Spindle A and spindle B melanomas were lumped together as spindle melanomas in the modified classification, and necrotic and fascicular variants were deleted.
- 7.
What is the most common cell type?
Most medium or large melanomas that are enucleated and examined histopathologically are mixed-cell tumors that contain a mixture of spindle and epithelioid cells. Eighty-nine percent of the melanomas that were enucleated in the Collaborative Ocular Melanoma Study (COMS) were mixed-cell tumors.
- 8.
How are melanoma cell types distinguished histopathologically?
Melanoma cells are readily differentiated by the characteristics of their nuclei. Spindle A cells have long, tapering cigar-like nuclei, an absent or indistinct nucleolus, and a characteristic longitudinal stripe caused by a fold in the nuclear membrane. Spindle B nuclei are oval and plumper and have less finely dispersed chromatin and a distinct nucleolus ( Fig. 51-2 ). Epithelioid cell nuclei are typically round and vesicular and have a prominent reddish-purple nucleolus ( Fig. 51-3 ). The chromatin is coarse and often clumps along the inside of the nuclear membrane (peripheral margination of chromatin). Spindle melanoma cells grow as a syncytium, making it difficult to discern the cytoplasmic margins of the bipolar fusiform cells. Epithelioid cells are poorly cohesive and their cytoplasmic margins are readily discernible.
Figure 51-2
Spindle B melanoma cells.
Figure 51-3
Epithelioid melanoma cells.
- 9.
Which cell type has the worst prognosis?
The presence or absence of epithelioid cells in a uveal melanoma has an important effect on prognosis. If no epithelioid cells are present, the expected survival at 15 years is 72%. If epithelioid cells are present (mixed, epithelioid, or necrotic cell type), the survival at 15 years drops to 37%. A tumor composed entirely of spindle A cells is now considered to be a benign nevus incapable of metastasis. Tumors composed entirely of epithelioid cells have the worst prognosis. Overall, approximately 50% of patients with uveal melanoma will die from their tumors.
- 10.
What special new tests are powerful prognostic indicators for patients with uveal melanoma?
Special new tests that are powerful prognostic predictors for patients with uveal melanoma include:
- 1.
Assessment for nonrandom chromosomal anomalies in the tumor cells;
- 2.
Gene expression profiling.
Nonrandom chromosomal abnormalities including loss of chromosome 3 and gains in chromosome 8 are associated with metastatic death. Monosomy 3 is 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 can be identified using a variety of techniques including fluorescence in situ hybridization and DNA amplification and microsatellite assay.
Gene expression profiling (GEP) of uveal melanomas by microarray analysis has disclosed two classes of tumors that differ markedly in their potential for metastasis. Class I melanomas are low-grade tumors with less than 5% risk for metastasis. In contrast, patients with class II melanomas have a greater than 90% risk for metastasis. The GEP of class II melanomas resembles primitive neural/ectodermal stem cells. They typically have other high-risk features including epithelioid cells, vascular mimicry patterns, and monosomy 3. GEP is available as a proprietary commercial test.
- 1.
Size
Ciliary body involvement
Cell type
Extraocular extension
Mitotic activity
Lymphocytic infiltration
Vascular mimicry patterns
Nonrandom chromosomal abnormalities (monosomy 3—poor prognosis)
Gene expression profile (class 2—poor prognosis)
- 11.
What is the most common site of metastatic uveal melanoma?
The liver is the most common site. Liver metastases occur in 93% of patients who develop metastatic uveal melanoma. Other sites include the lungs (24%) and bone (16%).
- 12.
What was the Collaborative Ocular Melanoma Study?
The COMS was a large prospective, randomized, multicentered study funded by the National Eye Institute that investigated the treatment of choroidal malignant melanoma. The arm of the study that focused on medium-sized tumors compared survival after enucleation and radioactive iodine 125 ( 125 I) plaque brachytherapy. The large tumor study compared survival after standard enucleation and enucleation preceded by external beam radiotherapy.
- 13.
What were the results of the COMS?
The medium-sized tumor arm of the COMS showed that survival was similar after both enucleation and plaque brachytherapy. The large tumor arm showed that “sterilization” of large melanomas with preenucleation external-beam radiotherapy did not improve survival.
- 14.
How are most uveal melanomas treated?
Today, most posterior uveal melanomas are treated with radioactive plaques. Plaque-treatment failures and eyes with larger tumors and/or tumor-related complications, such as secondary glaucoma or extrascleral extension, are still enucleated. Some smaller tumors are locally resected or treated with transpupillary thermotherapy (TTT). In some cases TTT is used to supplement plaque therapy.
- 15.
How effective is treatment of posterior uveal melanoma?
Treatment of uveal melanoma merely achieves local control and is relatively ineffective from the standpoint of survival. All forms of treatment seem to have little effect on decreasing subsequent death from metastases. It is thought that, unfortunately, most tumors already have metastasized before they are treated. Treatment for metastatic melanoma also is ineffective. Smaller tumors have a better prognosis and a lower incidence of monosomy 3 and class 2 GEP. Hence, the treatment of tumors while they are still small theoretically might be efficacious.
- 16.
What clinical features suggest that a small pigmented choroidal tumor is a melanoma?
The mnemonic “To Find Small Ocular Melanoma Using Helpful Hints Daily” refers to the clinical factors that suggest that a small pigmented tumor is a melanoma that is likely to grow, therefore putting the patient at greater risk for metastasis:
T for thickness greater than 3 mm
F for subretinal fluid
S for symptoms
O for orange pigment
M for margin touching optic disc
UH for ultrasound hollow
H for no halo
D for drusen absent
Choroidal melanocytic tumors that display none of these factors have only a 3% risk of growth at 5 years and most likely represent choroidal nevi. More than 50% of tumors with two or more risk factors grow, and they probably represent small choroidal melanomas. Early treatment of such lesions generally is indicated.
- 1.
Caucasian patients at greater risk
- 2.
Mushroom shape
- 3.
Spindle and epithelioid cells
- 4.
Liver metastases
- 5.
A 50% mortality rate
- 17.
Do iris melanomas behave differently?
The prognosis of iris melanoma generally is excellent (4 to 10% mortality). Most pigmented tumors of the iris are benign spindle-cell nevi. Overall, only 6.5% will enlarge during a 5-year period of observation. Most are low-grade spindle cell tumors, although iris melanomas do contain epithelioid cells occasionally.
Clinical features that suggest that a pigmented iris tumor is a melanoma include documented tumor growth, elevated intraocular pressure, hyphema, large tumor size, and tumor vascularity. Although they can occur anywhere, melanomas arise most frequently in the inferior sun-exposed part of the iris.
- 18.
What clinical features suggest that a uveal tumor is a metastasis?
Uveal metastases usually are creamy yellow amelanotic tumors that have a placoid or nummular configuration. Pigment mottling may occur on the tumor apex. Metastases are often multiple but can be solitary. Metastases usually cause a nonrhegmatogenous serous detachment of the retina with shifting subretinal fluid.
- 19.
What is the most common site of uveal metastasis?
Uveal metastases involve the choroid 81% of the time. They typically are found in the region of the macula where the choroidal blood supply is richest.
- 20.
What primary tumors are responsible for most uveal metastases?
Most uveal metastases come from breast carcinoma in women and lung carcinoma in men. Breast carcinoma is responsible for more than half of all ocular metastases. Nearly one-fifth are caused by lung cancer. Most women with uveal metastases from breast tumors have a history of breast carcinoma. In contrast, uveal metastasis may herald the presence of an occult lung cancer.
- 21.
How is immunohistochemistry (IHC) used to assess uveal metastases?
Primary uveal melanomas usually can be distinguished from uveal metastases using routine light microscopy. When a metastasis is found in a patient with no prior history of cancer, IHC often can suggest the identity of the primary tumor. For example, breast and lung cancers frequently stain positively (i.e., are immunoreactive) for cytokeratin 7 (CK7) and are negative for CK20. In contrast, most gastrointestinal cancers are CK20 positive. Immunoreactivity for specific markers that are expressed only by certain cancers is particularly helpful. Examples include the BRST2 marker in breast carcinoma, the TTF1 marker in lung cancer, and PSA and PSAP in prostate cancers.
IHC also is used as a prognostic marker and a guide to therapy. For example, breast carcinomas that express estrogen receptors can be treated with tamoxifen and aromatase inhibitors, whereas tumors that express HER/2neu can be treated with trastuzumab (Herceptin).
- 22.
What types of hemangiomas occur in the choroid?
Choroidal hemangiomas are classified as capillary, cavernous, or mixed. They are composed of thin-walled vessels and have little stroma ( Fig. 51-4 ). Sporadic hemangiomas tend to be discrete, localized, elevated reddish-orange tumors. The choroidal hemangiomas that occur in patients with Sturge-Weber syndrome are typically diffuse with indistinct tapering margins. These obscure the underlying choroidal architecture and impart a “tomato ketchup” appearance to the fundus.
Figure 51-4
Choroidal hemangioma.
- 23.
If choroidal hemangiomas are benign, why are they treated?
Choroidal hemangiomas are treated to save vision or the eye itself. Although they are benign from a systemic standpoint, choroidal hemangiomas cause retinal detachment and secondary glaucoma via iris neovascularization and/or a papillary block mechanism. The latter can lead to loss of the globe. Hemangiomas usually are treated with photodynamic therapy or laser photocoagulation.
- 24.
How does retinoblastoma typically present in the United States and Europe?
In the United States and Europe, retinoblastoma typically presents with leukocoria (a white pupillary reflex). Smaller tumors that involve the macula initially may present with strabismus. All children with strabismus should have a careful fundus examination to exclude retinoblastoma or other significant macular pathology. In developing countries, children often present in an advanced stage of the disease with a large orbital tumor secondary to extraocular extension.
- 25.
How old are patients when diagnosed with retinoblastoma?
The mean age at diagnosis is 18 months. Patients who have the familial form of the disease (i.e., who have germ-line mutations) are diagnosed earlier (mean age 12 months), probably because only a solitary “hit” or gene inactivation is required. Sporadic somatic cases occur in slightly older patients; they are diagnosed at a mean age of 24 months.
- 26.
What does retinoblastoma look like grossly?
Grossly, retinoblastoma has a distinctly encephaloid or brainlike appearance. This is not surprising because the tumor arises from the retina, which is a peripheral colony of brain cells. Foci of dystrophic calcification occur in many retinoblastomas. These foci of calcification are evident grossly as lighter flecks.
- 27.
What is an exophytic retinoblastoma?
Retinoblastoma shows several growth patterns. Exophytic retinoblastoma arises from the outer retina and grows in the subretinal space, causing retinal detachment ( Fig. 51-5 ). Endophytic retinoblastoma arises from the inner layers of the retina, which remains attached ( Fig. 51-6 ). Endophytic tumors invade the vitreous and may seed the anterior chamber, forming a pseudohypopyon of tumor cells. Most large retinoblastomas exhibit a combined endophytic/exophytic growth pattern. The diffuse infiltrative growth pattern is relatively rare and occurs in older children. The retina in such cases is diffusely thickened without a distinct tumefaction.
