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

We monitor many small, indeterminate pigmented choroidal tumors for three reasons: (1) as mentioned above, it is usually not possible to determine (with the exceptions noted below) which tumors will remain stationary and which will grow;

(2) in over 500 cases we have followed up, without signs of growth, many for as long as 10 years, no mortality has occurred. In those lesions that eventually grew, the tumor-related mortality has been < 5 percent, 5 years after treatment.77 In the later group of patients who were followed until growth was documented, there is no evidence to suggest

that delaying therapeutic intervention increases mortality rates, compared with rates in patients who have been treated elsewhere with immediate intervention;78,79 and (3) there is a morbidity associated with any form of treatment. Two subsequent large trials have found relatively similar results. As part of the collaborative ocular melanoma study, there was a significantly higher death rate from other causes than tumor, and in their analysis (with slightly different size inclusion criteria) the 8-year melanoma mortality was 3.7 percent. Similarly, a study by Shields and colleagues that included some

small active melanoma on first visit also had similar tumor-related mortality. 80

Many tumors, especially with extensive drusen, retinal pigment epithelium (RPE) hyperplastic changes, hypopigmented surround, or subretinal neovascularization, remain stationary for many years, and it seems reasonable to not intervene.77 Figures 7–26 and 7–27 document an exception to a rule, a tumor in which growth occurred in the presence of extensive, overlying drusen. Similarly, other exceptions to rules can occur, such as small melanomas that were treated and the patient died with metastases, or those with extraocular extension noted at enucleation.81–83 Fortunately, such cases are rare.

It is very difficult to differentiate a small melanoma (< 10 mm in diameter and < 3 mm thick) from an atypical nevus, and we have therefore labeled these lesions, with a neologism, termed “nevomas.” There are five inclusion criteria for patients to be serially examined without therapy:

1.tumor size (< 10 mm diameter and < 3 mm thickness),

2.the presence of good vision,

3.absent or minimal subretinal fluid,

4.informed consent, and

5.willingness to have frequent serial examinations, including fundus photography and ultrasonography.

A small amount of subretinal fluid just over a tumor can come and go; however, our experience has been that most tumors with dependent fluid are

active and should be treated. Figure 7–28 shows typical RPE changes inferior to a tumor due to resorbed subretinal fluid. Signs that suggest tumor activity are extensive orange pigmentation or an area of the tumor apparently entering a vertical growth phase (Figure 7–29). Figures 7–30A and B show a similar case followed up with 20/20 vision until growth occurred. At that juncture, the tumor was irradiated.

Figure 7–25. A 10-year follow-up without change in this 7.5 x 7.5 x 2.6 mm lesion. At autopsy, this lesion consisted of benign nevoid cells.

As discussed above, almost all patients with presumed nevomas versus small uveal melanomas are initially monitored clinically (indirect ophthalmoscopic fundus drawing and visual field) and have both photography and ultrasonography performed. The first two visits are usually spaced approximately 3 months apart. During the first year, if no growth is documented horizontally by photography or vertically by ultrasonography, patients are examined every

3 months. After the first year, the interval between return visits is gradually increased.

It is difficult, even with quantitative echography and serial fundus photographs, to be certain whether a very small amount of growth has occurred. Usually, when definite growth occurs, it is readily apparent on clinical observation as well as with ancillary tests (Figure 7–31). The accuracy of ultrasonographic measurements depends on equipment, operator skill, tumor topography, and melanoma loca-

tion.84,85 In regularly shaped posterior pole lesions, a quantitative A-scan increase of 0.5 mm is probably significant. In anterior lesions or in those with an irregular surface contour, ultrasound differences of < 1 mm have to be interpreted cautiously. Similarly, differences in the film, lighting, and camera technique mandate caution, unless the change on serial photographs is unequivocal.

We retrospectively reviewed approximately 300 nevoma patients.77 In approximately two-thirds of patients, the tumor did not grow over a 5-year observation. We developed a five parameter model to predict growth (Figure 7–32). Each of the factors was given 1 point, except for tumor height, for which 1 point was given for each millimeter of tumor thick-

ness. Symptoms, tumor thickness, presence of orange pigment, hot spots on fluorescein angiography, and homogeneity on ultrasonography were measured. A score of 1 to 2 was associated with < 10 percent chance of tumor growth versus over 90 percent likelihood if a score of 5 or more was established. In approximately 100 cases where the melanoma grew, there were 5 tumor deaths. In 3 of these, the patients delayed therapy despite recommendations for intervention. In one case, the tumor was initially seen when it was 1mm thick; the patient refused enucleation until the tumor filled the eye and became painful. In patients who allowed prompt intervention when growth was detected, the 5-year tumor-related mortality was < 3 percent.73

On the basis of our data and these studies, we no longer monitor all nevomas; if they have a score of 4 or more on our risk table, especially if they are distant from the optic nerve or fovea, we promptly treat them.77

Augsburger reviewed the literature on small melanocytic lesions, and noted that between 12 and 44 percent had growth documented; lesions classified as “dormant melanomas” had a 50 percent rate of enlargement.86 Other investigators have published slightly discrepant results, compared with our nevoma data, probably due to differences in case selection.68,80 In our analysis, we only included small, indeterminate lesions. As an example, a melanocytic tumor with orange pigment and subretinal fluid was promptly treated. Shields and colleagues reviewed over 1,000 small melanocytic tumors and noted that those with orange pigment, symptoms, contiguity to the optic nerve, increased thickness or subretinal fluid were more likely to grow.87 More cases developed metastatic disease (35 of 1,329); however, probably this reflects the selection criteria used and the percentage of metastatic events was similarly low.

INVASIVE DIAGNOSTIC TESTS

The use of invasive diagnostic tests is appropriate when therapeutic intervention is indicated and when

noninvasive test results are unclear. For example, in a patient with a growing lesion, with nondiagnostic clinical, ultrasound, and fluorescein angiographic findings, additional tests are indicated.

The radioactive phosphorus uptake test is no longer used because of its limited sensitivity and specificity in diagnostically difficult cases. It was routinely positive in large uveal melanomas that were easy to diagnose clinically or with ultrasonography. Its accuracy in atypical simulating lesions including atypical nevi, hemangioma, and metastases was limited.88,89

In difficult cases, in which therapeutic intervention is necessary but the diagnosis cannot be established with noninvasive tests, FNAB is the most useful diagnostic assay. There have been over 100,000 fine needle biopsies reported in the systemic cancer literature with no increased tumorrelated mortality.90 A complete discussion of the history and principles of FNAB is found in Chapter 15. In a recent study, we retrospectively reviewed, with the use of Cox multi-variate analysis, the effects of FNAB on melanoma-related mortality and found no adverse effect.91

A few case reports of tumor spread with largebore needle biopsies for solid intraocular tumors were published in the early 20th century through the 1950s. Since the late 1970s, a number of

authors have reported FNAB diagnosis of uveal melanomas.

FNABs are especially useful in patients with opaque media or atypical lesions that require intervention because of their size but cannot be definitively diagnosed with other tests.7,109 We use a 25-gauge needle, via the transvitreal or trans-scleral route, with minimal morbidity. Surprisingly, when we have used the transvitreal route and entered the tumor by piercing the retina, we have not produced a rhegmatogenous retinal detachment in those eyes that have subsequently undergone alternative therapy. When we use a trans-scleral approach directly over the tumor, we carefully isolate and dry that area and, as we remove the needle, close the minipuncture sites with a drop of histoacryl tissue adhesive.

We have not had any false-positive FNABs. In a few large necrotic melanomas, a false-negative diagnosis was obtained. In 5 small growing tumors, we did not establish a cytopathologic diagnosis. In a few atypical simulating lesions, we have been able to correctly differentiate a benign tumefaction from melanomas.7,108 We have established an FNAB diagnosis on growing adenomas of the ciliary epithelium, melanocytomas, uveal lymphoid tumors, various metastases, and a probable choroidal neurilemmoma. As a general rule, a positive FNAB result is useful, but a negative one, especially if there is an inadequate sample (too few cells), is not helpful. Other

investigators have noted some false-positive and false-negative results.103,109,111

The most important expertise in a FNAB is that of a superb cytopathologist. We have examined a number of specimens that were incorrectly diagnosed in other hospitals; if cytologic expertise is not available, this approach should not be used. It is invaluable to have a cytopathologist in the operating room. We immediately perform a quick stain on all aspirates. There are two reasons for this procedure: (1) we can establish the cytologic diagnosis in the operating room in over 98 percent of cases; and (2) if an inadequate specimen is obtained, a second biopsy can be performed. The attendance of a cytopathologist has resulted in a much lower false-negative rate than has been observed in other series.103,111

A number of adjuvant studies can be performed on cells obtained with FNAB techniques, including laboratory studies to assess DNA content, cell cycling, flow cytometry, ultrastructure, special stains, and fluorescent in situ hybridization (FISH) analysis. In a study of FNABs performed in eyes treated with either brachytherapy or charged particles, the cytopathologic determination of cell type was strongly correlated with prognosis.112 It is also possible to perform cell cycling studies on FNAB specimens.113 In one histologic study of irradiated eyes, positive cycling, as measured with a PC-10 antibody, was associated with ineffective radiation.112 In addi-

tion, we have recently shown using multivariate anaylsis that data from FNABs add important prognostic information in addition to other paramenters in nonenucleated eyes.91

There has been no evidence of spread of a nonocular malignancy caused by FNAB when a 23-gauge

or smaller needle was used. Even when extremely malignant, noncohesive animal tumors in syngeneic hosts are studied, no adverse effects on tumorrelated mortality as a result of FNAB have been reported. While tumor cells can be observed in the needle track of such animals or in some human sites,

too few cells are present to either develop a successful implant or spread elsewhere.114

Figure 7–33A shows an example of an atypical carcinoid tumor; FNAB correctly categorized the lesion (Figure 7–33B), and it completely regressed with a much lower radiation dose and no morbidity. If this tumor had been treated with standard radiation for a melanoma, significant ocular morbidity would probably have occurred. In our experience, we have been able to differentiate spindle, mixed, and epithelioid melanomas on cytopathology. Figure 7–34 shows a mixed melanoma (note both the spindle and epithelioid cells), while Figure 7–35 is a epithelioid melanoma.

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