Oncology

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Chapter 69 Oncology

Chapter outline

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Uveal malignant melanoma: Introduction

Jerry A. Shields and Carol L. Shields

General considerations

Uveal malignant melanoma is the most frequent intraocular malignancy encountered in a practice of ophthalmology1,2.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.

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.

The less common diffuse iris melanoma has a tendency to produce acquired hyperchromic heterochromia and secondary glaucoma due to tumor infiltration of the trabecular meshwork1. 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 clinically1 (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.

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.

Differential diagnosis

The differential diagnosis of uveal melanoma is discussed in more detail elsewhere1. 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.

Pathology

Most pathologists use the Mclean modification of the Callender classification, in which uveal melanoma is divided into spindle, epithelioid, and mixed cell types1. 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.

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 enucleation7. 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 melanoma8,9. Other radioisotopes have been utilized for brachytherapy including cobalt-60, palladium-103, and iridium-192.

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 plaque9. 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.

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.

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 neuropathy13,14.

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.

Proton beam radiotherapy of uveal melanoma

Ann Schalenbourg and Leonidas Zografos

Goals of treatment

As the treatment through which local tumor control is achieved (enucleation or conservative therapy) has no influence on its metastatic risk22, 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) melanomas17,20, whereas others reserve this modality for tumors that cannot adequately be treated conservatively by brachytherapy or local resection19,23. 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.

Proton beam radiotherapy

A total dose of 60–70 Cobalt Gy-equivalent is delivered in four to five fractions16,17. 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.

Assessment of surgery

Because survival is usually predetermined by the time the ocular tumor is detected and treated22; 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 melanoma17,1921,26,27. 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.

Stereotactic photon beam radiation techniques for uveal melanoma

Martin Zehetmayer and Richard Poetter

Assessment of treatment-related adverse side effects

Acute side effects are negligible. As with brachytherapy and proton beam radiotherapy treatment-related, long-term adverse side effects include optic neuropathy, maculopathy, cataract, exudative retinal detachment, and neovascular glaucoma.

The success of treatment is assessed according to local tumor control, visual impairment, other adverse side effects and quality of life. Fractionated SRT leads to an actuarial rate of local control of 95% at 5 years. As with other forms of therapy for uveal melanoma, the influence of ocular treatment on survival is uncertain. Survival rates after SEBI are similar to those of other therapies.

Fractionated LINAC SRT is increasingly being used and is similar in principle to the proton therapy approach. At present, most centers use 50–70 Gy total dose delivered in five fractions with 14–10 Gy per fraction313335.

An unanswered question is whether a moderate total dose delivered with single fraction SRS is superior or inferior to a fractioned somewhat larger total dose in SRT, in terms of local control and morbidity.

Both methods seem to produce similar results with regards to local control; however, the therapeutic window of single-fraction SRS with the GammaKnife seems to be narrower. High single-dose treatment (e.g. 50–80 Gy) was abandoned because of common and severe complications38,39. Single radiation doses below 40 Gy (at the tumor margin) seem to lead to high local tumor control rates with an acceptable incidence of radiogenic side effects29,30,34,39.

Beside the total dose, there is evidence that the amount of irradiated eye and tumor volume influences outcome28.

With Cyberknife SRS, early good results are reported with a 22–18 Gy prescribed marginal dose36.

It is worth mentioning that SEBI technologies are relatively cost effective because they are non-invasive, or minimally invasive, and because they require less capital outlay than methods such as proton beam radiotherapy. They are usually administered on an outpatient basis. Furthermore, surgery is not needed, unlike proton beam radiotherapy, which requires tantalum marker insertion, and in contrast to brachytherapy, which involves surgical insertion and removal of the radioactive plaque.

Further studies are required to determine whether SEBI should be combined with endoresection and, if so, in which cases.

Local resection of uveal melanoma

Bertil Damato, Heinrich Heimann and Carl Groenewald

Indications

Primary local resection

Iridectomy is indicated for nodular melanomas involving up to 4 clock hours of iris and not extending to angle. In several centers, this has been replaced by brachytherapy or proton beam radiotherapy40.

Iridocyclectomy is performed for tumors involving up to 4 clock hours of angle and/or ciliary body and is preferred to radiotherapy when tissue is desired for diagnosis and/or prognostic studies (Fig. 69.11)40.

Trans-scleral choroidectomy and cyclochoroidectomy are performed in few centers and then only if the tumor is considered unsuitable for radiotherapy because the thickness is too great for brachytherapy, and if proton beam radiotherapy or stereotactic radiotherapy is undesirable because of risks such as optic neuropathy or canalicular obstruction40,41. Contraindications to trans-scleral local resection are: diffuse tumor spread, extensive retinal invasion, extraocular spread, involvement of optic nerve or more than 4 clock-hours of the ciliary body, and poor general health precluding hypotensive anesthesia (Fig. 69.12).

Endoresection is indicated for posterior tumors up to 10–13 mm in diameter as a means of avoiding radiation-induced optic neuropathy or maculopathy if the patient is keen to retain good vision and accepts the controversial nature of this surgery (Fig. 69.13).