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

170 TUMORS OF THE EYE AND OCULAR ADNEXA

tion of patients treated with either protons or helium ions has demonstrated ocular complications both inside and outside the radiation field. Uveal melanoma patients whose tumors are distant from the fovea and the nerve can still develop loss of vision after charged particle therapy. The data from both Boston and San Francisco demonstrate that tumor thickness is a major factor in determining whether patients will or will not have good posttreatment vision, independent of the tumor’s location and the radiation field dose to the nerve or the fovea. Figure 8–53A demonstrates a case of a peripheral uveal melanoma treated with helium ion irradiation, where neither the optic nerve nor the fovea received any significant radiation. Unfortunately, 8 months later, the visual acuity was permanently diminished, secondary to an exudative detachment into the fovea. Since untreated large melanomas may produce rubeosis iridis, cystoid macular edema, and other visually destructive complications, it is unclear whether the post-radiation distant effects, as shown in Figure 8–53B, are due to irradiation or the tumor itself or its regression response after treatment.203

Similarly, it is apparent that post-treatment neovascular glaucoma and cataracts occur mainly with large melanomas and develop as complications, as a result of direct radiation damage to the anterior segment as well as tumor size.168,177,204–206 Anterior segment neovascularization can be difficult to diagnose, since it has a much greater predilection for the

Figure 8–48. Radiation-induced exudates.

chamber angle rather than the anterior iris surface. All patients with elevated intraocular pressures should have gonioscopy. The glaucoma in many of these cases can be controlled with steroids, glaucoma medications, and retinal ablation (panretinal photocoagulation or cryotherapy) procedures.

Radiation: Conclusion

Our experience of both particle and plaque therapies demonstrates some advantages and disadvantages of these techniques. Larger melanomas are more advantageously treated with proton therapy than with any form of radioactive plaque. If melanomas > 18 mm in diameter and > 10 mm thick are not removed, they should be managed with charged particle irradiation.

Figure 8–50. Acute radiation optic neuropathy.

Unfortunately, < 15 percent of irradiated eyes with tumors of that thickness retained 20/200 or better vision, and approximately 25 percent of such eyes are eventually enucleated from late complications.

There is usually less external eye damage if thick posterior uveal melanomas are treated with radioactive plaques. Shielding the 125I plaque with a gold carrier minimizes damage to the adnexal structures, which, depending on tumor position, include the lacrimal gland, puncta, and eye lashes. There may be more intraocular radiation damage, such as radiation retinopathy, with plaques. Lesions contiguous to the optic nerve head are more difficult to treat with plaques than with particles. Radiation complication rates associated with the treatment of larger anterior melanomas are high.207

Several molecular biologic approaches are being studied to attempt to decrease radiation ocular morbidity. However, there is a paucity of even phase I ophthalmic data. In vitro, alteration of the manganese superoxide dismutase gene alters relative damage to the tumor, compared with normal cells.208 Similarly, alterations of the Egr-1 gene appear to alter the relative effect on normal versus tumor cells.209,210 Several studies have addressed the mechanisms of radiation-induced vascular compromise; however, clinical trials are just being initiated.211,212 Vascular central nervous system (CNS) injuries have shown some response to anticoagulation, but the effectiveness of this approach in radiation-induced injury is uncertain.213,214

Adjunctive Hyperthermia

Hyperthermia, which has been known to have anticancer properties since the 19th century, has a synergistic effect with radiation.215–217 A number of investigators have used hyperthermia to treat animal models of intraocular melanoma, and a few patients have been treated. Laboratory data have also demonstrated that heat can alter the antigenic array on uveal melanoma in vitro.218 Initial longterm results reported by Finger and colleagues looked promising;219 however, patients in that series were derived from highly selected cases, with approximately two-thirds having good prognosis both for vision and life, and the results should

Figure 8–51. Radiation optic atrophy with vascular closure after cobalt plaque therapy.

Figure 8–52. Lash loss and both conjunctival and lid erythema occur within the first 6 weeks after charged paticle irradiation, when the lids are included in the treatment field.

172 TUMORS OF THE EYE AND OCULAR ADNEXA

A

B

Figure 8–53. A, Large peripheral melanoma treated with helium ion radiation. B, Exudative changes in the macula 8 months after treatment of the above peripheral uveal melanoma. Both the fovea and the optic nerve were outside the radiation treatment field.

therefore have been excellent.219 There is little evidence to suggest that this approach has been demonstrated to increase the control rate or decrease the morbidity, compared with radiation alone. It is also uncertain whether it will be better to use ultrasound, microwave, laser, or ferromagnetic seed-induced hyperthermia to treat ocular tumors, if this modality is used. In a collaborative European systemic hyperthermia study, technical problems with therapeutic delivery were noted; only 14 percent of cases received optimal heating.220 Several groups, including ours, have shown in animals that there is at least a two-fold enhancement of radiation effect with heating.221,222 Therefore, it is likely that if there will be a role for hyperthermia, a markedly reduced radiation dose will

have to be given in order to avoid the complications that previously have been noted.

Enucleation

The efficacy of enucleation in the management of uveal melanoma has been controversial for many years. Early workers noted widely discrepant survival rates after enucleation; between 20 to 96 percent of patients died as a result of the tumor.223,224 Some investigators believed that early enucleation decreased tumor-related mortality, while others did not.224–226

Zimmerman and colleagues suggested a potentially deleterious effect of enucleation on tumorrelated mortality.227,228 There are a number of data that demonstrate that enucleation does not adversely affect prognosis.229,230

Zimmerman and his colleagues hypothesized that pressure on the eye during enucleation could seed tumor cells into the circulation and increase the risk of metastases. In one hamster model, there were data consistent with this viewpoint, but not in another animal model.231,232 Retrospective clinical pathologic data from the Armed Forces Institute of Pathology (AFIP) demonstrated that the peak incidence of metastases occurred during the first 2 years after enucleation, and the researchers inferred that the increased risk of metastases during this time period could be due to surgical manipulation.

There are a number of data that do not support that hypothesis. (1) Several other malignancies treated with nonsurgical techniques have a similar tumorrelated mortality curve; an adverse effect from surgical trauma cannot be used to explain these data.233 (2) Some of the statistics used to advance the argument are open to question. (3) As previously mentioned in the section on metastatic evaluation, the AFIP data can be equally explained by the hypothesis that there are undetectable micrometastases at the time of enucleation.230 (4) If myelin artifact, as evidence of a more traumatic enucleation, is used, there is no correlation between that finding and patient survival.231 (5) The data available from charged particle irradiation partially refute the hypothesis. If pressure at the time of surgery were a major factor in promoting metastasis, it is likely that those patients treated with charged particle beams, in whom tantalum marker rings are

often sutured at the posterior of the globe, would be at greater risk for metastases than those patients who underwent enucleation. Retrospective matched studies comparing enucleation and proton beam irradiation have shown that the latter technique appears to have a lower incidence of metastases.112 (6) Animal studies have demonstrated that pressure alone at the time of enucleation is not enough to increase tumorrelated mortality.112

Prior to considering a patient as a candidate for enucleation, we perform a metastasis evaluation. If a patient has uveal melanoma metastases, the mean survival is < 1 year, and enucleation should not be performed, unless the eye is painful.

It is important to establish a correct diagnosis before enucleation is considered. As previously discussed, using modern diagnostic techniques, falsepositive enucleation for suspected melanomas should occur in < 1 percent of cases. In the last 10 years, we have not enucleated any eyes in which the diagnosis of uveal melanoma was not confirmed on histopathologic examination.

In an eye with a suspected large melanoma with opaque media or in other very atypical cases, we perform either trans-scleral or transvitreal FNAB with a 25-gauge needle. As the needle is withdrawn from the sclera, the area is sealed with histoacryl glue. The cytologist in the operating room can usually make the diagnosis immediately (Figure 8–54); if the biopsy is positive for melanoma, the eye is enucleated.

Enucleation is the recommended therapy for a number of uveal melanomas. It should be used in patients who, after informed consent, request removal of the eye. It is also best in patients whose melanoma involves over 40 percent of ocular volume or over 50 percent of the ocular circumference. Our experience has demonstrated that while such tumors can be destroyed with charged particle irradiation, visual function is lost.139 If the melanoma is associated with significant neovascularization or is in a blind eye, the eye should be enucleated.

Surgical Procedure

There are a number of enucleation techniques. We usually perform a standard enucleation with minimal pressure on the eye. We have not used a cryoenucle-

ation technique. It is unwieldy; if one were a strong advocate of this procedure, it would be necessary to perform a lateral orbitotomy to insert the cryo-appa- ratus against the tumor area of the eye with minimal trauma.232 We do not use a paracentesis to decrease intraocular pressure during eye removal.233

A 360° limbal peritomy is performed (Figure 8–55). The quadrants are gently opened, using a Bishop Harman forceps and Steven’s scissors, to separate Tenon’s capsule from the globe and isolate the muscles (Figure 8–56). If there is a previously undetected area of extraocular extension, we routinely isolate the Tenon’s capsule in that quadrant and extirpate it, along with contiguous extraocular muscle, and the globe en bloc.234 In this situation, since some of these cases are treated with adjunct radiation, 50 Gy can result in loss of the implant and some cosmetic defect.

In routine enucleation, the four recti muscles are isolated and detached. We routinely use scleralwrapped hydroxyapatite (HA) integrated implants, and the muscles are imbricated with 5-0 vicryl (Figure 8–57).235 If an older approach with only a sphere is used, the muscles are severed from the globe. Regardless of technique, we leave 2 mm stumps of the medial and lateral recti muscles on their insertions. After the recti and oblique muscles are severed from the globe, the two stumps are used to grasp the globe, using either 4-0 silk sutures or mosquito forceps (Figure 8–58). We usually use forceps instead of sutures in a resident teaching institution, since we are concerned about the possibility of penetrating a tumor-filled eye with a suture needle. A Steven’s or curved enucleation scissors is placed into the medial orbit after the optic nerve is located using a Steven’s muscle hook. The blades of the scissors are placed around the optic nerve, and it is severed (Figure 8–59). A test tube filled with warm water is placed in the orbit; a 4 × 4 sponge is used to create pressure for approximately 7 minutes. It is not necessary to use an optic nerve snare for hemostasis, and not using it avoids some myelin artifacts on histologic sections.

After enucleation, the eye should be carefully examined in the operating room. If there is a significant area of extraocular extension which had not been noted during the enucleation procedure, the orbit is explored using Sewell retractors. If a small area of extraocular extension was transsected

at the time of enucleation, the gross residual tumor should be removed and no implant inserted into the orbital space.

In adults, we generally use a 20-mm HA implant soaked in antibiotic solution and 0.5 percent bupivacaine (Marcaine). An allogenic scleral shell from which the cornea has been harvested is sutured with 5-0 dacron so that the corneal space is facing posteriorly. Windows, approximately 3 × 5 mm in size, are cut through the sclera at the equator (Figure 8–60).

When hemostasis is achieved, the implant is placed in the orbit. If a scleral-wrapped HA implant is used, the ends of the horizontal and vertical muscles are imbricated into the respective anterior lip of each scleral window, as shown in Figure 8–61.

If an older implant is used, the largest size compatible with the patient’s orbital anatomy is selected; in adults, a 20or 22-mm sphere or a large Moore or Ellis implant is inserted (Figure 8–62). In infants or children, implant size varies between 14 and 20 mm.

If an older modified Ellis or Moore implant is used instead of a sphere, the horizontal muscles are imbricated together and the vertical muscles are imbricated together over the surface of the implant (Figure 8–63). This should not be done with a plain sphere, since it will cause implant migration. Tenon’s

capsule is closed in three layers. A 4-0 chromic suture or 4-0 vicryl is used in a “purse-string” manner (Figure 8–64A). Two rows of interrupted 4-0 chromic suture are used to close the remaining gaps in Tenon’s capsule (Figures 8–64B and C). The conjunctiva is closed with a running 6-0 plain gut suture (Figure 8–64D).

A conformer is placed into the orbit, approximately 2 mL of 0.75 percent bupivacaine is then injected into the orbital quadrants, and the orbit is

Figure 8–55. A 360° peritomy with relaxing incisions.

Figure 8–56. A Stevens scissors is used to open Tenon’s capsule between the rectus muscles.

firmly pressure-patched for approximately 48 hours. The use of an injectable long-acting anesthetic markedly reduces postoperative pain, and many patients leave the hospital either the same day or the morning after surgery. The patch is removed at 48 hours, and the patient is then repatched for an additional 48-hour period. After that time, the orbital dressing is changed daily by the patient.

We have not used a dermis-fat graft as a primary procedure after enucleation for two reasons:

(1) We do not believe that it markedly enhances

cosmesis; and (2) there is continual remodeling, and in tumors where there might be a question of local recurrence, this has led to confusion in a number of cases.236,237

The patient is examined by an ocularist within 2 weeks after enucleation so that the painting of the orbital prosthesis can be begun. The fitting of the orbital prosthesis generally occurs between 4 and 8 weeks after surgery.

While HA implants are now in vogue, their ultimate role in enucleated sockets is uncertain.238–240 These are expensive, can rarely become exposed, and do not always produce better cosmesis than a much less expensive plastic or silicone sphere.241 Several newer synthetic implants that may be less expensive and equally effective have become available.242 Some of the results with these approaches have been less effective.243 An advantage of the HA implant is that it is easy to shape in the operating room, if contour alteration or size reduction is required.244 Several complications have been reported with HA implants, especially when they are pegged for better motility. The discussion of that cosmetic approach is outside the scope of this book. In the author’s experience, less than one-half of the patients require pegging to obtain excellent motil- ity.245–253 After either enucleation or, more often, exeneration, placement of an orbital epidermal catheter may be useful to control discomfort.254.

176 TUMORS OF THE EYE AND OCULAR ADNEXA

Figure 8–58. The stumps of the medial and lateral rectus muscles can either be grasped with mosquito forceps or, as shown, imbricated with 5-0 silk traction sutures.

Adjunctive Pre-enucleation Radiation

While several groups were questioning the usefulness of pre-enucleation radiation, we initiated a phase I/II trial, whose design was the basis for a portion of the COMS in 1977. In patients with large uveal melanomas scheduled for enucleation, 20 Gy of pho-

ton irradiation was given in five 400-cGy fractions over 1 week.245,246 In some systemic malignancies, the use of perioperative irradiation has decreased tumorrelated mortality. Anterior lateral wedge pair ports were used, as shown in Figure 8–65. Either on the final day of irradiation or on the following day, enucleation was performed. We observed no significant untoward effects with this fractionation schedule and radiation dose.246 The theoretical advantages of such an irradiation dose were (1) it has been shown to be effective in other malignancies; (2) melanomas appear to be more responsive to relatively high fraction sizes (400 cGy) rather than conventional (200 cGy) fractionation; (3) 20 Gy given in high fraction sizes is probably as effective as 30 Gy given with conventional size fractions; (4) this dose and fractionation schedule could be delivered in a short period, whereas increasing radiation to 40 Gy would entail 6 weeks of radiation; and (5) this dose and fractionation were safe and entailed little risk to the uninvolved contiguous structures.

There are a number of potential limitations to this approach. (1) If micrometastases have already occurred at the time of diagnosis, it is unlikely that ocular irradiation will decrease tumor-related mor-

tality. (2) The dose and fractionation schedule chosen, while reasonable, may be inadequate to destroy the tumor. (3) Perioperative irradiation has been most effective in tumors in which there has been either local or lymph node recurrence; this is not the pattern for uveal melanoma spread.

Unfortunately, although the rationale for this study seemed reasonable, the approach proved to be ineffective in our experience. We used Cox model analysis to compare the survival of 42 patients treated with this protocol with 33 patients with similar tumors enucleated by the same surgeon.247 Tumor size, cell type, and use of pre-enucleation irradiation were all significant parameters associ-

ated with worse prognosis. The data indicate that pre-enucleation irradiation did not improve survival. The failure of this technique does not appear to be

178 TUMORS OF THE EYE AND OCULAR ADNEXA

Figure 8–63. If an integrated implant is used, the medial and rectus muscles are tied together, as are the superior and inferior rectus muscles. The four rectus muscles are then imbricated together in a circular fashion to avoid slippage. If a sphere is used and the muscles are not tied over the implant, migration is inevitable.

due to inadequate radiation dose, since irradiated tumor cells had significantly less tumor culture growth or cell cycling than had cells from nonirradiated melanomas. On the basis of these data, we have abandoned this modality.

Luyten and colleagues used two 400-cGy fractions in 145 cases and used Cox model analysis to compare them with a historic control group; no improvement in survival was noted.248 Similarly, four other trials found no beneficial effect with preenucleation radiation.249,255–257

The COMS reported its results in a prospective randomized trial of enucleation versus pre-enucle- ation radiation followed by enucleation in 1,003 patients (pre-encleation radiation of 497 and enucleation alone in 506 patients). They found no statistically significant difference in the 5-year survival in the two groups. While there was slightly better survival in the group that received radiation,

the difference and balances in the baseline covariates may have accounted for this. A few were biopsied for recurrence in the eyes that received preenucleation radiation versus enucleation alone (0 versus 5), and surprisingly, the patients who received radiation had a slightly lower incidence of ptosis. However the author thinks that the latter finding was probably spurious.258

Exenteration

There are very few indications for exenteration in uveal melanoma, even when there is focal, extraocular extension.259 If there is diffuse extraocular extension, then exenteration is indicated to remove the tumor, provided there are no metastases (Figure 8–66). Often, these patients have metastases. The patient shown in Figure 8–67 was referred for exenteration of an orbital recurrence; however, metastatic evaluation revealed widespread disease. Prior to exenteration, a complete metastatic evaluation is performed. Exenteration can be performed either with lid-sparing or non–lid sparing techniques (Figures 8–68 to 8–79). I prefer to remove the lids at the time of exenteration in uveal melanoma cases. We have managed a few patients with local recurrences that, after exenteration, were controlled because they were detected very early, since the only volume in the orbit was a split-thickness skin graft. If we had elected to do surgery and had chosen to spare the lids, allow self-granulation, or place a temporalis flap, the tumor would have grown beyond local control by the time it was noted.

Surgical Procedure

Exenteration techniques, for both sparing and removing of the lids, are shown (see Figures 8–68 to 8–79). If the eyelids are to be retained, a skin incision is made with a No. 15 blade scalpel in the upper and lower lids, approximately 2 mm from the eyelash margin. The skin is mobilized, and a myocutaneous flap elevated to the area of the orbital rim in all directions (see Figures 8–68 and 8–71). If the lids are to be sacrificed, then an incision is made just inside the orbital rim with a scalpel (see Figures 8–69 and 8–72). Using a cutting Bovie, the incision

is carried down to the orbital rim for 360°. A Bovie cautery along with mosquito clamps is used to achieve hemostasis. The orbital rim is incised with a scalpel; Freer elevators are used to undermine the periosteum for 360° (Figure 8–73). Scissors are used to cut the medial and lateral canthal tendons. The periosteum is elevated to the orbital apex, and the orbital contents are cut and removed, using curved scissors. Hemostasis is achieved with Bovie cautery, by obliterating flow in the ophthalmic artery and temporary packing. It is important to remove the lacrimal sac and avoid, if possible, creating defects in the adjacent sinuses.

If the lids have been removed, we obtain a splitthickness skin graft from the lateral aspect of the upper thigh. A Brown dermatome (or similar instrument) is used to harvest the graft, which is sutured with interrupted and running 6-0 silk around the outer aspect of the orbit to the remaining periorbital skin (see Figure 8–77). The graft is then placed against the orbital walls and sutured to itself. A pressure dressing of Xeroform gauze packing is left in situ for 7 days.

We change the dressing three times in the first month, each time leaving the dressing in place for 7 days, and then gradually decrease the pack over the next 2 weeks. This ensures the survival of the split-thick- ness graft, as shown in Figure 8–78. Since the splitthickness skin is not against any pressure-bearing surfaces, normal desquamation does not occur. The orbit should be cleaned by the patient, a family member, or a nurse every week, with a dilute solution of hydrogen peroxide and cotton tip applicators.

If the lid skin is left at the time of exenteration, we suture it together and put pressure against the skin to force it into contact with the walls of the orbit. We then pressure-pack with gauze and antibiotic ointment for approximately 7 days, and then gradually decrease the pressure and the pack.

The cosmesis achieved with any form of orbital implant after exenteration is limited. While the patient in Figure 8–79 appears to have reasonable cosmesis, the lids do not blink and the eye does not move. Most patients have not been willing to wear a prosthesis over extended lengths of time.