Uveal malignant melanoma is the most frequent intraocular malignancy encountered in a practice of ophthalmology ^1,².This neoplasm is important because of its potential to cause blindness and death due to systemic metastasis. Hence, clinicians should be familiar with uveal melanoma and make an accurate diagnosis and recommend referral to a subspecialist who manages this neoplasm. Approximately 85% of uveal melanomas arise in the choroid, 10% in the ciliary body, and 5% in the iris. This subchapter briefly discusses demographics, clinical features, differential diagnosis, diagnostic approaches, pathology, management, and prognosis for uveal melanoma.

Demographics

The annual age-adjusted incidence of uveal melanoma is six cases per 1 million population in the United States and Europe. Uveal melanoma is decidedly more common in adult Caucasians and is uncommon in children and dark-skinned individuals. In our experience with 8033 patients with uveal melanoma, the median age at presentation was 59 years (range 3 to 99 years) and the male/female ratio was 50/50%. The melanoma occurred in Caucasians in 98% cases followed by Hispanic (1%), African American (<1%), Asian <1%), Middle Eastern (<1%), Native American (<1%), and Asian Indian (<1%)³. Hence, it is diagnosed more often in Europe and America and infrequently in Africa and Asia. There is no predisposition for gender. Predisposing conditions for uveal melanoma include congenital ocular melanocytosis, Caucasian race, and possibly the dysplastic nevus syndrome and excess exposure to sunlight.

Clinical features

The clinical features of uveal melanoma are covered in detail in a comprehensive textbook and numerous articles on the subject ¹. The clinical findings vary with the location of the lesion in the uveal tract.

Iris melanoma

Iris melanoma can be circumscribed (nodular) or diffuse. Circumscribed iris melanoma appears as a variably pigmented, well-defined mass in the iris stroma (Fig. 69.1). More than 80% are located in the inferior half of the iris. It can be totally pigmented, partly pigmented, or clinically amelanotic. The size and shape can vary considerably from case to case. Some are relatively small and almost flat and others are larger and more elevated. Like iris nevus, which is generally smaller, it can cause an irregular pupil and ectropion of the pigment epithelium at the pupillary margin.

Fig. 69.1 Iris melanoma.

The less common diffuse iris melanoma has a tendency to produce acquired hyperchromic heterochromia and secondary glaucoma due to tumor infiltration of the trabecular meshwork ¹. It can diffusely affect the entire iris or it can appear as irregular geographic patches of pigment. Some patients with diffuse iris melanoma present with unilateral ipsilateral glaucoma and there is a delay in diagnosis while the ‘idiopathic’ or ‘pigmentary’ glaucoma is treated.

Ciliary body melanoma

In contrast to iris melanoma, ciliary body melanoma often attains a larger size before it is recognized clinically ¹ (Fig. 69.2A). However, it is frequently associated with external signs that suggest the underlying diagnosis. The most important is one or more dilated episcleral blood vessels (sentinel vessels) that develop over the base of the tumor. A second sign is an epibulbar pigmented lesion characteristic of transcleral extension of the tumor. When the pupil is dilated widely in such cases, the ciliary body tumor can be visualized as a dome-shaped mass (Fig. 69.2B). Less often, it can assume a circumferential ring growth pattern (ring melanoma). Ciliary body melanoma frequently causes subluxation of the lens and cataract. It can grow posteriorly into the choroid (ciliochoroidal melanoma) and anteriorly into the anterior chamber angle and iris (iridociliary melanoma). It can infiltrate the trabecular meshwork, causing secondary glaucoma.

Fig. 69.2 Ciliary body melanoma. A. Sentinel vessel and pigmented foci of extrascleral extension. B. Appearance of the pigmented ciliary body mass.

Choroidal melanoma

Choroidal melanoma usually presents as a sessile, dome-shaped, or mushroom-shaped mass deep to the sensory retina (Fig. 69.3). It is usually moderately or deeply pigmented but it can be entirely non-pigmented, in which case the diagnosis can be more difficult. A posterior choroidal melanoma can display clumps of overlying orange pigment on its surface at the level of the retinal pigment epithelium. A secondary non-rhegmatogenous retinal detachment frequently occurs. In contrast to a rhegmatogenous detachment, in which the subretinal fluid does not shift, the fluid with melanoma and other tumors shifts with positional changes of the patient’s head. When the melanoma is amelanotic and mushroom shaped, dilated blood vessels in the tumor are visible ophthalmoscopically. When a choroidal melanoma breaks through Bruch’s membrane and assumes such a mushroom shape, it has a tendency to bleed into the subretinal space and vitreous, often obscuring a view of the underlying tumor. Choroidal melanoma can also assume a diffuse growth pattern with only minimal elevation of the tumor¹.

Fig. 69.3 Choroidal melanoma superior to the optic disc in the right eye.

Differential diagnosis

The differential diagnosis of uveal melanoma is discussed in more detail elsewhere ¹. Iris melanoma can resemble iris nevus, epithelioma (adenoma) of the iris pigment epithelium, iris cyst, iridocorneal endothelial syndrome, leiomyoma, and miscellaneous other conditions. Ciliary body melanoma must be differentiated from tumors of the ciliary body pigmented epithelium and non-pigmented epithelium, leiomyoma, cyst, ciliochoroidal effusion, and several other tumors and pseudotumors. Pigmented choroidal melanoma can resemble a large choroidal nevus, subretinal hemorrhage, and a number of other tumors and pseudotumors. Non-pigmented choroidal melanoma must be differentiated from amelanotic choroidal nevus, choroidal metastasis, choroidal hemangioma, granuloma, and other conditions.

Diagnostic approaches

Iris melanoma can generally be diagnosed by slit-lamp biomicroscopy and gonioscopy. Ciliary body melanoma is more difficult to detect because of its hidden location. However, slit-lamp biomicroscopy, gonioscopy, transillumination, indirect ophthalmoscopy, ultrasound biomicroscopy, or standard ultrasonography generally discloses typical features. Choroidal melanoma is generally diagnosed by ophthalmoscopy. In atypical cases, fluorescein angiography and ultrasonography may assist in diagnosis. Atypical iris, ciliary body, or choroidal lesions can undergo fine needle aspiration biopsy with cytopathology study to confirm or exclude the diagnosis of melanoma.

Pathology

Most pathologists use the Mclean modification of the Callender classification, in which uveal melanoma is divided into spindle, epithelioid, and mixed cell types ¹. Most iris melanomas and smaller posterior uveal melanomas are predominantly of spindle cell type, whereas larger melanomas contain a greater proportion of epithelioid cells. Histopathologic criteria for a worse prognosis include more epithelioid cells, greater mitotic activity, greater basal diameter of the tumor, diffuse growth pattern, and extrascleral extension of the melanoma. Genetic factors related to poor prognosis include chromosome 3 monosomy, especially with 8q addition.

Management

Management of uveal melanoma depends on several clinical findings and includes close observation, laser ablation, transpupillary thermotherapy, plaque brachytherapy, charged particle irradiation, local resection, enucleation, and a combination of methods. Plaque radiotherapy and enucleation are the two most commonly employed methods, with the goal being complete eradication of the malignancy. Studies comparing both methods have found similar survival rates ⁴.

Prognosis

Useful features for predicting prognosis for vision and life are mentioned above and described elsewhere. Recently, cytogenetic alterations in uveal melanoma cells have emerged as the most reliable methods of predicting systemic prognosis. Monosomy of chromosome 3 and gain in chromosome 8 (trisomy 8) are most reliable for predicting a worse prognosis ^5,⁶. These are also discussed in more detail elsewhere.

Summary

This brief introductory subchapter has outlined demographics, clinical features, differential diagnosis, diagnostic approaches, pathology, management, and prognosis for uveal melanoma. These topics are discussed in more detail elsewhere in this textbook and in the literature.

Brachytherapy of uveal melanoma

Tara A. McCannel and Bertil Damato

Introduction

Uveal melanoma has traditionally been treated by enucleation, plaque brachytherapy, or external beam radiation with local resection or phototherapy in some cases. Brachytherapy with iodine-125 and enucleation have been evaluated prospectively in a multi-centered fashion by the Collaborative Ocular Melanoma Study (COMS). The COMS did not show mortality rates for medium-sized melanomas to be significantly worse after iodine-125 plaque brachytherapy than after enucleation ⁷. Brachytherapy with iodine-125, which delivers gamma irradiation, is the favored treatment modality in the United States because it has good tissue penetration and its short half-life contributes to its ease of use. Furthermore, the dosimetry can be adjusted for each individual tumor by adjusting the number and distribution of the iodine-125 seeds, which are embedded in the resin lining the underside of the shell. In Europe, ruthenium-106, which mostly emits beta irradiation, is the preferred radioisotope for local treatment of uveal melanoma^8,⁹. Other radioisotopes have been utilized for brachytherapy including cobalt-60, palladium-103, and iridium-192.

Fundamental principles

The objective of brachytherapy for uveal melanoma is to deliver a dose of at least 80 Gy to all parts of the tumor and to the adjacent choroid, while minimizing collateral damage to the optic nerve, fovea, lens, and other ocular structures.

Goals of surgery

The goal of brachytherapy is to control local tumor growth by sterilizing the primary tumor while conserving the eye with as much useful vision as possible. It is not known whether brachytherapy or any other form of treatment for uveal melanoma alters patient mortality and if so in whom. Furthermore, treatments for metastatic uveal melanoma are not usually effective ¹⁰.

Indications for surgery

Uveal melanomas up to 5 mm thick can be treated with a ruthenium-106 plaque, and tumors up to 10 mm thick may be treated with an iodine-125 plaque ⁹. Tumors beyond 20 mm in the largest basal dimension are difficult to treat with episcleral plaque. Brachytherapy is also contraindicated by bulky extraocular extension, unless such tumors can be excised. Optic nerve involvement is not necessarily a contraindication if dosimetry suggests that the entire tumor can be irradiated. Notched iodine-125 plaques can be designed to allow adequate treatment to the nerve¹¹.

Preoperative assessment

In addition to a comprehensive ophthalmic and systemic evaluation, the tumor height and basal dimensions must be determined for radiation dosimetry. Indirect biomicroscopy and ultrasonography are useful means to obtain tumor dimensions. Routinely, the radial and transverse dimensions, tumor thickness, and distance from the optic nerve and fovea are obtained.

Anesthesia

Surgery may be performed under local or general anesthesia, according to the surgeon’s and patient’s preference.

Operation techniques

A 180–360° conjunctival peritomy is made and the sclera overlying the tumor is exposed. The rectus muscles are isolated and looped with 2-0 silk suture for scleral exposure. The muscles may be disinserted and preplaced on hang-back sutures to allow for adequate placement of the plaque. The tumor margins are localized by transillumination or indirect ophthalmoscopy and marked on the sclera with a pen.

Ruthenium-106 plaque

In Liverpool, 15 mm, 20 mm, and 25 mm ruthenium plaques are used for tumors with basal diameters not exceeding 10 mm, 15 mm, and 20 mm respectively. The intended location of the anterior plaque edge is marked on the sclera. A transparent template with four perforations is sutured to the sclera with releasable sutures and its position in relation to the tumor is checked by performing binocular indirect ophthalmoscopy with a right-angled 20-gauge transilluminator passed through the posterior perforation of the template. With tumors extending close to optic disk or fovea, the template is placed with its posterior edge at the posterior tumor margin. Once the template is correctly positioned, a mattress suture is placed in the sclera and left loose. The template is removed and replaced by the radioactive plaque, which is secured by sutures (Fig. 69.4). If trans-scleral tumor biopsy is performed (e.g. for genetic tumor typing), this is done after tumor localization and immediately before inserting the radioactive plaque. If the biopsy is trans-retinal, this is undertaken after radioactive plaque insertion.

Fig. 69.4 Radioactive plaque in position.

The plaque is removed once the desired radiation dose has been delivered. Some prescribe a dose of 80–90 Gy to the tumor apex, irrespective of the dose to base. The author (BD) prescribes a minimum dose of 350 Gy to the sclera and a minimum apex dose of 85 Gy. Various dosimetry software programs exist.

Iodine plaque

At the Jules Stein Eye Institute in Los Angeles, a thinner modified COMS plaque has evolved with dosing and dimensions customized to each individual patient tumor. Plaque placement is similar to that for ruthenium plaques, with transillumination performed to mark the anterior edge of the tumor. Confirmation of plaque placement by indirect ophthalmoscopy is particularly helpful in treating amelanotic uveal melanomas. The author (TM) performs routine intraoperative ultrasonography before permanent tying of the plaque sutures. This has been demonstrated to increase the accuracy of plaque placement and potentially reduce the risk of marginal local recurrence ¹².

Intraoperative complications

Retinal perforation may occur while placing scleral sutures and may be treated by laser or cryotherapy. Softening of the globe with vitreous loss associated with this complication can be primarily managed with injection of balanced salt solution with a 30-gauge needle at the pars plana prior to evaluation by a vitreoretinal surgeon.

As with other surgical procedures for uveal melanoma, special care is necessary when performing transillumination, to avoid being misled by penumbras and amelanotic tumor extensions.

Postoperative care

Standard radioisotope precautions include wearing a lead eye-patch during the plaque placement period and avoiding unnecessary exposure to crowds of people. Restrictions are otherwise limited by any ocular discomfort and most patients may perform their usual activities.

Postoperative complications

Short-term complications include ptosis and diplopia, which frequently resolve by 6 months. Blepharoplasty or strabismus surgery may be considered if these problems persist.

Long-term complications include local tumor recurrence and radiation side effects. Marginal tumor recurrence is identified by lateral tumor extension, as indicated by comparing ophthalmoscopic appearances with baseline color photographs. Central tumor recurrence is demonstrated by increasing tumor thickness on repeated echography. This may be treated by further radiotherapy, local resection, or enucleation.

Iodine-125 emits relatively low energy photons, which theoretically decreases radiation-related complications. In spite of this favorable profile, iodine-125 brachytherapy can cause keratitis, cataract, neovascular glaucoma, maculopathy, and optic neuropathy ^13,¹⁴.

Maculopathy is a frequent complication of plaque brachytherapy regardless of the location of the treated melanoma. To date, the management of this complication remains discouraging. Exudative maculopathy may be treated by transpupillary thermotherapy administered to the tumor (without safety margins), photodynamic therapy, intraocular anti-angiogenic agents, intraocular steroids, or tumor excision by endoresection or trans-scleral excision. Visual loss from radiation-induced optic neuropathy is the second most common complication and has not been shown to satisfactorily respond to therapies.

Occasionally brachytherapy of a large melanoma is followed by neovascular glaucoma and a blind painful eye requiring enucleation.

Assessment of surgery

The main quality indicator of brachytherapy is local tumor control. Following brachytherapy, the tumor size may vary within the first 2 months due to local inflammation. Ultrasonography may be performed at the 3-month postoperative visit to confirm a tumor response. Either stabilization of tumor growth or a decrease in tumor height by ultrasonography is considered a successful response to brachytherapy (Fig. 69.5). Rapid shrinkage of the melanoma actually portends a poor prognosis for the patient¹⁵.

Fig. 69.5 Superonasal choroidal melanoma in the left eye of a 60-year-old woman. (A) Preoperatively, the tumor measured 13.9 mm in basal diameter with a thickness of 3.5 mm. (B) Five months postoperatively, the tumor thickness had diminished to 2.1 mm. The visual acuity remained good at 20/17.

Proton beam radiotherapy of uveal melanoma

Ann Schalenbourg and Leonidas Zografos

Introduction

External beam radiotherapy has the advantage over brachytherapy in delivering a uniform irradiation to the target volume. Additionally, its indication is less restricted by size, shape, and/or location of the tumor. Teletherapy can be delivered through photons (X-rays), electrons, gamma rays, or accelerated heavy particles (protons, alpha particles). Proton therapy was first applied in Boston in 1975 ¹⁶, in Lausanne and the Paul Scherrer Institut (PSI) in 1984^17,¹⁸, and is becoming available in a growing number of centers around the world¹⁶^–²¹.

Fundamental principles

Protons cause maximal ionization at the place where they are absorbed (‘Bragg’s peak’). They are produced by a cyclotron, modulated and collimated, before reaching the patient, who is immobilized with the eye gazing in a fixed direction. An advantage of protons is the sparing of uninvolved eye tissues outside the collimator. Consequently – in order to avoid marginal recurrence – the tumor mass needs to be precisely localized through prior surgical insertion of tantalum markers.

Goals of treatment

As the treatment through which local tumor control is achieved (enucleation or conservative therapy) has no influence on its metastatic risk ²², the main goal of protontherapy is to achieve maximal local tumor control while conserving a comfortable eye, and, if possible, useful residual vision.

Indications for proton beam radiotherapy

Some centers use proton therapy for nearly all uveal (iris, ciliary body, and choroidal) melanomas ^17,²⁰, whereas others reserve this modality for tumors that cannot adequately be treated conservatively by brachytherapy or local resection^19,²³. In all centers, contraindications include: tumor volume of more than 50% of the eye, large extraocular extension, (sub)total retinal detachment, suspicion of optic nerve invasion and neovascular glaucoma.

Preoperative assessment

A general check-up (including blood tests, ECG, chest X-ray, and liver imaging) is performed. Specific examinations include photographic documentation of the tumor and an ultrasonic evaluation of its dimensions. The axial length of the globe is measured to generate a personalized computer model of the eye.

Anesthesia

Insertion of tantalum markers is done under local or general anesthesia, whereas proton therapy is administered with topical anesthesia.

Operation techniques for tantalum marker insertion

A 180–360° conjunctival peritomy is made. The eye is rotated with muscle slings or, if any rectus muscles have been disinserted, with traction sutures placed in the sclera. The tumor margins are localized by transillumination and marked on the sclera with ink or a pen. Transparent tumor margins are visualized by indentation and indirect ophthalmoscopy. Tantalum markers, four to seven in number, are sutured to the sclera close to the tumor margins (Fig. 69.6A). These buttons are 2.5 mm in diameter, inert, and non-magnetic. Measurements are taken of distances from each marker to: (i) the nearest tumor margin, (ii) the other markers, and (iii) the limbus. The limbus diameter is also recorded. Any disinserted muscles are reinserted and the conjunctiva is closed in the usual fashion.

Fig. 69.6 (A) Transillumination showing the base of a ciliochoroidal melanoma surrounded by markers. (B) Irradiation plan (beam view) showing the eye with the tumor (in red) surrounded by a 2 mm lateral safety margin. (Numbers 1–5 indicate the position of markers.)

Simulation

A face-mask and a bite-block are molded for each patient, to immobilize the head precisely in a frame that is secured to the delivery apparatus. The position of the patient’s chair is adjusted so that the tumor is in the target area. Radiographs are taken to localize the tantalum markers for computerized modeling of the tumor within the eye. A brass collimator is prepared for each patient, with an opening adapted to the projected tumor shape (Fig. 69.6B). The irradiation depth can be modulated by interposing absorbers in the proton beam trajectory. The optimal ocular position is determined, so that minimal doses of radiation are delivered to optic disc and other structures.

Proton beam radiotherapy

A total dose of 60–70 Cobalt Gy-equivalent is delivered in four to five fractions ^16,¹⁷. The patient is seated with the head immobilized by the mask and bite-block, gazing at a strategically located target. The eyelids are usually retracted with a speculum. However, when the upper eyelid margin cannot be avoided, treatment is sometimes administered through closed eyelids, the patient fixating with the other eye.

Intraoperative complications

Intraoperative complications are rare, the most evident being retinal perforation when suturing a marker to the sclera. The most common is an over- or underestimation of the tumor margins on transillumination. A penumbra caused by oblique transillumination can cause an overestimation of the tumor extent. Conversely, relative differences in tumor pigmentation as well as the parallax phenomenon – the fact that the posterior tumor margin, to the tangentially placed observer’s eye, is projected about 1 mm anteriorly on the external scleral face – are responsible for an underestimation of the tumor margins ²⁴.

Postoperative care

Postoperative care is the same as for other extraocular procedures.

Postoperative complications

Postoperative diplopia, related to the manipulation of extraocular muscles, usually resolves spontaneously.

Short-term radiation-induced complications include dermatitis of the irradiated part of the eyelids. The severity of the post-radiation uveïtis and associated increase of serous retinal detachment depend on the target volume.

Long-term complications such as radiation-induced optic neuropathy, maculopathy, and cataract can usually be predicted at the time of treatment planning and therefore occur unavoidably when the tumor extends close to those structures ²⁵.

Maculopathy caused by edema or hard exudates can occur even when the macula receives little or no radiation. The risks of persistent retinal detachment and neovascular glaucoma increase with tumor volume ¹⁸.

There is growing interest in treating radiation-induced complications with anti-angiogenic agents, laser treatment, and local resection of the irradiated tumor.

Though the lacrimal gland is systematically avoided in the irradiation plan, patients can experience a difference in lubrification of their eye, related to irradiation of the mucous surface glands or the canaliculi.

Assessment of surgery

Because survival is usually predetermined by the time the ocular tumor is detected and treated ²²; the main quality indicator is local tumor control (Fig. 69.7). Local tumor recurrence ranges from 1–5% and figures among the lowest of conservative treatment techniques for uveal melanoma^17,¹⁹^–²¹ ^,26 ^,27. Marginal tumor recurrence can occur if tumor extent is underestimated, which can occur with tumors involving ciliary body. Central tumor recurrences are rare. Conservation of the eye is mainly related to tumor dimensions, the main cause of secondary enucleation being neovascular glaucoma²⁰. Residual vision depends on tumor location and size rather than the type of conservative therapy.