Ординатура / Офтальмология / Английские материалы / Tumors of the Eye and Ocular Adnexa_Char_2001

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85.Grossniklaus HE, Martin DF, Avery R, et al. Uveal lymphoid infiltration report of four cases and clinicopathologic review. Ophthalmology 1998;105: 1265–73.

86.Strempel I. Rare choroidal tumor simulating a malignant melanoma. Ophthalmologica 1991;202:110–14.

87.Shields JA, Font RL, Eagle RC, et al. Melanotic schwannoma of the choroid. Immunohistochemistry and electron microscopic observations. Ophthalmology 1994;101:843–9.

88.Ben-Ezra D, Sahel JA, Harris NL, et al. Uveal lymphoid infiltrates: immunohistochemical evidence for a lymphoid neoplasia. Br J Ophthalmol 1989;73: 846–51.

89.Fan JT, Robertson DM, Campbell RJ. Clinicopathologic correlation of a case of adenocarcinoma of the

retinal pigment epithelium. Am J Ophthalmol 1995; 119:243–5.

90.Fredrick DR, Char DH, Ljeung BM, Brinton DA. Solitary intraocular lymphoma as an initial presentation of widespread disease. Arch Ophthalmol 1989;107: 395–7.

91.Jurgens I, Roca G, Sedo S, et al. Presumed melanocytoma of the macula. Arch Ophthalmol 1994;112: 305–6.

92.Barondes MJ, Sponsel WE, Stevens TS, Plotnik RD. Tuberculous choroiditis diagnosed by chorioretinal endobiopsy. Am J Ophthalmol 1991;112:460–61.

93.Eide N, Syrdalen P, Walaas L, Hagmar B. Fine needle aspiration biopsy in selecting treatment for inconclusive intraocular disease. Acta Ophthalmol Scand 1999;77:448–52.

Making the correct diagnosis in suspected uveal melanomas is a function of observer experience, media clarity, and tumor size. In most ocular oncology practices, over 99 percent of tumors that require therapeutic intervention can be correctly diag- nosed.1–6 The diagnostic accuracy reported in various series is partially predicated on the criteria used. In a recent study, we noted that 9 of 100 small to medium uveal tumors that were scheduled for radiation therapy on a basis of a noninvasive test diagnosis of uveal melanoma did not have that diagnosis confirmed with fine-needle aspiration biopsy (FNAB).7 In another series, findings from a fine-needle biopsy altered the therapeutic plan in 48 percent of the cases.2 In our experience with uveal melanomas that have required enucleation, there has been < 1 percent diagnostic error rate.1 A recent publication from the Collaborative Ocular Melanoma Study (COMS) cited an even lower diagnostic error rate; however, the difficult diagnostic cases, such as those with opaque media, were excluded from that analysis since the COMS inclusion criteria included a readily diagnosable melanoma to be part of that study.8 In small centers, the diagnostic accuracy is less. In 5 of 53 eyes enucleated with the diagnosis of a uveal melanoma by community ophthalmologists in Florida, another diagnosis was noted on histologic examination.9

It is almost impossible to differentiate a small melanoma from a large, atypical nevus; patients with such small, indeterminate lesions 1 to 3 mm thick are usually monitored. Very few physical findings are pathognomonic for the diagnosis or exclusion of a

small uveal melanoma. Pragmatically, we often classify indeterminate pigmented lesions < 10 mm in diameter and < 3 mm thick as “nevomas.” Clinically, it is difficult to distinguish tumors that will grow from those that will remain stable for many years. The fluorescein pattern is not diagnostic, and on ultrasonography, while homogeneity is most often associated with a potentially active small melanoma, it is not pathognomonic.10 Gass and others have stressed that certain clinical features, such as subretinal neovascularization, drusen, and a hypopigmented surround, are signs of chronicity; however, the author has observed indeterminant pigmented choroidal lesions with each of these features which demonstrated growth.6 Therefore, even when factors associated with chronicity are noted, the lesions are still closely monitored.

Uveal melanoma pigmentation is variable; there is usually some intrinsic tumor pigmentation, although 25 percent of cases are amelanotic. Most melanomas are light to medium gray in color; a moderately elevated (< 4 mm) black lesion is more likely to be either a melanocytoma or an extramacular disciform lesion, especially if there is significant vitreous hemorrhage.11,12 Some clinicians have used transillumination to differentiate melanomas with intrinsic pigmentation from other simulating lesions. I do not use transillumination diagnostically for posterior tumors. I have seen histologically documented uveal melanomas that do not block transillumination and nonmelanoma lesions that do. As previously mentioned, orange pigmentation over melanomas is quite common.6,13 A typical pattern is shown in Figure 7–1 in a small

lesion that eventually grew and was treated. The orange pigmentation may be discrete or confluent and may vary in its intensity.

There are a number of typical clinical, ultrasonographic, and photographic features for medium (10 to 15 mm diameter and 3 to 5 mm thick) and large uveal melanomas (> 15 mm in diameter or > 5 mm in thickness). Interestingly, there are different definitions now in use for small, medium, and large tumors. The COMS considers a small tumor < 16 mm in diameter, and < 3 mm thickness. A large tumor is > 16 mm diameter or > 10 mm thick.14 Figure 7–2 demonstrates a large uveal melanoma with the typical collar button (“mushroom shaped”) appearance that occurs when the tumor breaks through Bruch’s membrane. This topography is almost pathognomonic for a uveal melanoma. Retinal invasion is often associated with a collar button configuration; on ophthalmoscopic examination, the melanoma surface appears velvety brown atop the collar button (Figure 7–3). Uncommonly, a dense vitreous hemorrhage occurs secondary to a uveal melanoma that has broken through Bruch’s membrane (Figure 7–4).8 If a mass is < 5 mm thick, a Bruch’s membrane rupture is unlikely; a dense vitreous hemorrhage in such cases is more suggestive of an extramacular or macular disciform process, although a melanoma must be ruled out.15

Figure 7–5 demonstrates a histologically benign lesion simulating this process.

Usually, eyes with large choroidal melanomas have an associated exudative retinal detachment. Occasionally, an area of choroidal detachment is also present.15 Figure 7–6 shows a large, relatively amelanotic melanoma, with almost 30 percent of the retina secondarily detached. It is sometimes difficult to differentiate a rhegmatogenous from an exudative

Figure 7–3. Retinal invasion in an area in which the melanoma has broken through Bruch’s membrane. Clinically, retinal invasion has a typical velvety surface texture.

retinal detachment. Four features are helpful in differentiating these conditions: (1) retrolental detachments (Figure 7–7), (with the exception of those associated with proliferative vitreo-retinopathy), are almost never rhegmatogenous; if the retina is easily visible on routine slit-lamp biomicroscopy, the detachment is almost always secondary to tumor or inflammation;

(2) exudative detachments have shifting subretinal fluid margins; the fluid pools inferiorly when the

patient is upright and superiorly if the patient is placed with his head down; (3) subretinal fluid associated with a melanoma is usually quite clear and the retinal marking distinct. Often, these exudative detachments can be either missed or mistaken for retinoschisis by an inexperienced observer; this clarity of retinal detail is also observed in some longstanding rhegmatogenous detachments. It is quite common for smaller melanomas to have subretinal fluid, either just over the tumor or visible only in the

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inferior fundus; this is most easily detected by indirect ophthalmoscopic examination to identify elevated retinal vessels; and (4) patients with exudative detachment do not have retinal holes, although a careful fundus examination will detect retinal breaks in as many as 6 percent of uveal melanoma patients, an incidence comparable with that in the general population.

A variant of the more common globular-shaped choroidal melanoma is the diffuse uveal melanoma which has an increased predilection for extraocular extension.16 The most common definition of this lesion is that it involves at least 25 percent of the uveal tract and is < 5 mm thick.17 A diffuse melanoma simulating a large atypical nevus is shown in Figure 7–8.

Ultrasound evaluation is the most useful diagnostic test in the evaluation of patients with elevated uveal mass lesions, especially those > 3 mm in thickness. A complete description of ultrasound technique and analysis is beyond the scope of this book; a number of excellent reviews have been writ- ten.18–20 We have found that a combination of both immersion B-scan and Kretz A-scan (quantitative echography) are most reliable. Their performance and interpretation are acquired skills; for the novice, pattern recognition is a good first step in differentiating choroidal lesions. Figure 7–9A shows an immersion B-scan of a uveal melanoma. On quantitative echography (Figure 7–9B), the reflectivity of the tumor is medium to low. Vascular pulsations can often be observed during the actual performance of

Figure 7–8. A diffuse uveal melanoma (< 5 mm in thickness and involving at least 25 percent of the uveal tract).

this test. Figure 7–10 shows extrascleral extension of uveal melanoma.

In some centers, duplex sonography and color Doppler ultrasonography have also been used. No blood flow has been noted in choroidal nevi or agerelated macular degenerations, in contrast to uveal melanomas.20,21 This technique may also be useful to detect vascular changes that occur after radiation of the uveal melanomas.22–24 Several other ultrasound approaches for volume measurement have also been reported.25–28

A

B

Figure 7–9. A, An immersion B-scan showing the typical findings of a uveal melanoma including an acoustic quiet zone (*), choroidal excavation (arrow), and orbital shadowing (o). B, A quantitative A- scan demonstrating medium to low reflectivity which is characteristic of a uveal melanoma.

Figure 7–10. Immersion B-scan shows a uveal melanoma with localized extrascleral extension.

It is important to emphasize that in an eye with opaque media, ultrasonic biometry to establish IOL power cannot be used to exclude a uveal melanoma. We have examined a number of patients, including one in whom we removed a 12 mm thick ciliary body choroidal tumor with a cyclochoroidectomy, that had “normal” ultrasound biometry results. Others have noted similar problems with that technique.29,30

As mentioned previously, the diagnostic accuracy of fluorescein angiography in uveal melanoma diagnosis is less than 50 percent.1 Fluorescein angiographic findings suggestive of a choroidal melanoma are an intrinsic vasculature (Figure 7–11), “hot spots,” which are initially point-source leakage that became diffuse over time (Figure 7–12), vascular leakage, and blockage of fluorescence by orange pigment. Often, there are prominent tumor vessels in the collar-button portion of a melanoma (Figure 7–13). As mentioned in Chapter 6, confocal indocyanine green scanning laser ophthalmoscopy may allow evaluation of other prognostic factors that are currently not available in eyes in which histology has not been attained.31

Computed tomography (CT) (Figure 7–14) and magnetic resonance imaging (MRI) (Figure 7–15) both generate images of uveal melanomas and sim-

Figure 7–11. Fluorescein angiogram demonstrating an intrinsic vasculature (“double circulation”) in a large melanoma.

ulating lesions. In some cases, CT can detect extraocular extension of a choroidal melanoma (Figure 7–16); however, we have not noted significantly better sensitivity with either CT or MRI, compared with ultrasonography. Other workers have found that MRI is more sensitive for the detection of extraocular extension of a tumor, although the relative sensitivity of these techniques has not been proven.32 On MRI, the T1 and T2 parameters of uveal melanoma may be characteristic due to the melanin free radical. The typical appearance of a uveal melanoma on an MRI scan is hyperintense, in comparison with the

Figure 7–12. Fluorescein angiogram demonstrating “hot spots,” which initially are pointsource leakage, not window defects, which gradually show enlargement during the course of the study.

vitreous on T1–weighted and a hypointense image on T2–weighted scan (Figures 7–17A and B).33 Unfortunately, the pattern of a melanocytoma on MRI is identical to a melanoma.34–40

Subsequent studies reported different T1 and T2 patterns of uveal melanomas on MRI.35–40 As an example, a typical MRI pattern of a uveal melanoma has been reported in 7 to 93 percent of cases.37 Clearly, some of these differences are due to equipment or imaging strategies; however, MRI is much less cost effective than ultrasonography and does not offer more information for the diagnosis of most

uveal melanomas.37–43 We initially thought that this technique might be very useful in differentiating a choroidal hemorrhage or an extramacular disciform from a uveal melanoma. Unfortunately, it is not always diagnostic. Figures 7–18A and B show the MRI pattern in an elderly patient who had multiple repeat dense hemorrhages. MRI was nondiagnostic, as was ultrasonography. The patient had a FNAB, which was also negative. The author felt the recurrent hemorrhage was due to the tumor and therefore removed the eye since it was not functional. On examination of the enucleated specimen, this was a

B

Figure 7–17. A and B, On T1-weighted MRI, the uveal melanoma is hyperintense to brain, while on T2-weighted scan it is hypointense.

necrotic melanoma with only a few viable cells in the midvitreous.41

Magnetic resonance spectroscopy has been described in uveal melanomas by several groups including ours. Currently, that technique, positron emission tomography (PET) scans, and immunoscintography with monoclonal antibodies directed toward melanoma-associated antigens are research tools.44–49 As discussed in Chapter 6, the data supporting the use of these imaging techniques in tumors < 7 mm in diameter and 5 mm thickness are tenuous.50,51

We use CT or MRI to confirm the extraocular extension noted on ultrasonography.47 An example of a melanoma in which the main tumor mass was extrascleral is shown in Figure 7–16. In our experience, small areas of extrascleral tumor extensions can produce false-negative ultrasound, CT, and MRI data.33

It is possible that a Doppler ultrasonography, PET, and 31P spectroscopy may improve our ability to accu-

A

B

Figure 7–18. A, MRI T1-weighted coronal scan shows a hyperintense uveal lesion in relation to brain. B, MRI T2-weighted coronal scan shows both hypeand hypointensity consistent with either a hemorrhage or a melanoma and intratumor hemorrhage.

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or review of systems) are confusing or when a patient is referred for a second opinion after an intraocular surgery with a presumed hemorrhage, and the true nature of the intraocular pathology was not correctly established. Figures 7–19 and 7–20 demonstrate one of these difficult diagnostic settings. In both cases, the patient was referred to superb retinal surgeons with presumed vitreous hemorrhages that had occurred after glaucoma or cataract surgery. Extraocular extension of both uveal melanomas had occurred after the surgeries.

METASTATIC EVALUATION

Approximately 1 percent of patients with uveal melanoma simultaneously present with both ocular and systemic disease.58,59 It is likely that many more patients have microscopic disease, but we are unable to detect it with current imaging and blood studies. The author has not seen a patient with a smallor medium-sized melanoma present with simultaneous metastases.

Microscopic tumor that has undergone only 10 to 15 doublings and is < 1 mm3 in size will be missed with current diagnostic modalities (ophthalmoloscopy, ultrasound, FNAB). If one assumes that the tumor starts as one malignant cell and that it takes approximately 40 doublings to kill a host, until a tumor is

Figure 7–19. Patient was referred for retinal evaluation because of vitreous hemorrhage following glaucoma seton surgery. The melanoma was not detected until extrascleral extension was noted.

Figure 7–20. Patient was referred for retinal evaluation because of vitreous hemorrhage following cataract surgery. Similar to the case in Figure 7–19, there was no underlying melanoma detected until extrascleral extension was noted.

“middle aged” and has gone through 20 doublings, it is not detectable.59

The rate of uveal melanoma tumor growth is uncertain, and probably it varies during the natural history of the tumor. We and others have used clinical and cell cycling studies to demonstrate that melanomas are relatively slow growing.60,61 Manschot speculated that it takes up to 7 years to develop metastases from an active uveal melanoma; however, that hypothesis assumes a constant doubling time.62 Folkman and colleagues have demonstrated that micrometastases are probably not initially vascularized, but while the cells are rapidly dividing, they are in “in equalibrium” with apoptosis.63

We studied the initial site of metastatic disease in enucleated uveal melanoma patients who developed clinically detectable metastases. The initial site of metastasis from primary uveal melanoma is shown schematically in Figure 7–21. The most common initial presentation for metastases is in the liver; approximately 60 to 70 percent of patients first develop liver metastases. Usually, these patients have right upper quadrant pain, fullness, tenderness, nausea, vomiting, and weight loss.58 Other less common presentations of metastatic uveal melanoma include subcutaneous nodules, lung disease, bone involvement, and central nervous system disease. In a subsequent study by Gragoudas and colleagues, 94 percent of patients with metastatic disease had liver involvement.64 In another study of 24 metastatic uveal melanoma patients, 87 percent had liver involvement, 46 percent

had lung lesions, 29 percent had bone lesions, and 17 percent had subcutaneous metastases.65

The sensitivity of radiologic imaging tests versus serum studies to detect metastases is unclear.66–68 A number of investigations have demonstrated that the serum lactic dehydrogenase (LDH) or glutamyl transpeptidase (GTP) have a false-negative rate of approximately 3 percent.69 In a study by Hicks and colleagues, the sensitivity of GTP was 21 percent with the specificity of 92 percent. In contrast, the sensitivity of ultrasonography was 14 percent. The relative sensitivity of serum tests versus chest-abdominal MRI or CT is unclear. All patients evaluated by the author receive standard chest radiography, liver function tests (alkaline phosphatase, LDH, GGP), and a general physical examination. If these preliminary studies are negative, we do not order other metastatic investigations. If the chest radiograph is positive, we obtain chest CT; if the liver function tests are positive (and there is a false-positive rate of up to 40 percent), we obtain body abdominal CT and use a FNAB if a lesion is noted. A study from Finland has disagreed with our approach. This was a retrospective cohort study. Interestingly, they diagnosed 74 percent of the metastases by screening; 26 percent were symptomatic. In that study, liver ultrasonography was diagnostic 78 percent of the time, while liver function tests were only abnormal in 70 percent of cases. More importantly, the false-negative rate was 33 percent with the serum liver function test versus 4 percent with ultrasonography. They also found that the use of chest radiography, given the relatively low pick-up, was not very cost effective.67 Typical liver metastases on liver CT is shown in Figures 7–22A and B. Rarely, other patterns of metastases can occur. We have managed a few patients with metastatic tumors of the opposite orbit. Figures 7–23A and B show a primary uveal melanoma that was irradiated. Two years later, the patient presented with a FNAB-diagnosed metastasis to the other eye as the initial manifestation of widespread disease (Figure 7–23A).

SERIAL OBSERVATION

WITHOUT INTERVENTION FOR NEVOMAS

The effect of intervention on uveal melanoma mortality has been controversial for over 100 years. 70–74 There have been a few patients who refused enucle-

CNS – 2%

Pulmonary – 7%

Liver – 56%

Vertebral – 7%

Subcutaneous – 24%

nodules

Figure 7–21. The initial site of uveal melanoma metastasis (Reprinted from Char DH. Metastatic choroidal melanoma. Am J Ophthalmol 1978;86:76–80).

ation for large, growing melanomas yet lived many years without the development of metastatic disease, although historically almost all untreated patients died of widespread disease.75,76

There is a reasonable amount of retrospective data that suggest that patients with small uveal melanomas or indeterminate pigmented tumors < 3 mm in thickness and < 10 mm in diameter can be safely monitored without therapeutic intervention until growth is documented.74 Figures 7–24A and B document a 10-year follow-up, without apparent growth of a pigmented tumor that remained 3.5 mm thick on quantitative echographic measurement. Figure 7–25 shows a similar lesion followed up for 10 years, until the patient died of a myocardial infarct. Histologic examination of the choroidal mass showed only benign pigmented cells.